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BACKGROUND: Immunotherapy represents a groundbreaking and monumental achievement in the field of cancer therapy, marking a significant advancement in fighting against this devastating disease. Lung cancer has showed consistent clinical improvements in response to immunotherapy treatments, yet, it is undeniable that challenges such as limited response rates acquire resistance, and the unclear fundamental mechanisms were inevitable problems. METHODS: The cellular composition was defined and distinguished through single-cell RNA sequencing (scRNA-seq) analysis of MPR (major pathologic response) and NMPR (non-major pathologic response) samples in GSE207422, including four primary MPR samples and eight primary NMPR samples. RESULTS: We found obvious difference in CD8+ T cell population between MPR and NMPR samples, with high expression of TYMS, RRM2, and BIRC5 in NPMR samples. Meanwhile, the proportion of macrophages and tumor epithelial cells infiltration increased in the NMPR samples. We discovered biomarkers (ACTN4, ATF3, BRD2, CDKN1A, and CHMP4B) in epithelial cells which were potentially represented worse outcomes. CONCLUSIONS: By exploring the difference of tumor microenvironment (TME) in samples with different corresponding degrees of neoadjuvant immunotherapy, this research introduces a number of novel biomarkers for predicting the response of treatment and a theoretical basis for overcoming immunotherapy resistance.
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Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Imunoterapia , Neoplasias Pulmonares , Análise de Célula Única , Microambiente Tumoral , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Imunoterapia/métodos , Análise de Célula Única/métodos , Biomarcadores Tumorais/genética , Análise de Sequência de RNA/métodos , Regulação Neoplásica da Expressão Gênica , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Perfilação da Expressão GênicaRESUMO
The white light interferometer is advantageous for wavelength division multiplexing (WDM), but the excessive noise floor limits its application in practicality. In this Letter, we propose a fiber-optic sensor driven by a broadband light source, which uses a fiber-optic Fabry-Perot cavity and a reference interferometer to enhance strain resolution. In the experiment, the strain resolution of a 5.86â m resonant sensor is 18.5â fÉ/H z at 1.5â kHz, while the maximum detectable signal is over 230â rad at 1â kHz. With low cost, this method provides a new, to the best of our knowledge, solution for WDM sensing arrays with a large dynamic range.
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BACKGROUND: The Ad5-nCoV vaccine is a single-dose adenovirus type 5 (Ad5) vectored vaccine expressing the SARS-CoV-2 spike protein that was well-tolerated and immunogenic in phase 1 and 2 studies. In this study, we report results on the final efficacy and interim safety analyses of the phase 3 trial. METHODS: This double-blind, randomised, international, placebo-controlled, endpoint-case driven, phase 3, clinical trial enrolled adults aged 18 years older at study centres in Argentina, Chile, Mexico, Pakistan, and Russia. Participants were eligible for the study if they had no unstable or severe underlying medical or psychiatric conditions; had no history of a laboratory-confirmed SARS-CoV-2 infection; were not pregnant or breastfeeding; and had no previous receipt of an adenovirus-vectored, coronavirus, or SARS-CoV-2 vaccine. After informed consent was obtained, 25 mL of whole blood was withdrawn from all eligible participants who were randomised in a 1:1 ratio to receive a single intramuscular dose of 0·5 mL placebo or a 0·5 mL dose of 5 × 1010 viral particle (vp)/mL Ad5-nCoV vaccine; study staff and participants were blinded to treatment allocation. All participants were contacted weekly by email, telephone, or text message to self-report any symptoms of COVID-19 illness, and laboratory testing for SARS-CoV-2 was done for all participants with any symptoms. The primary efficacy objective evaluated Ad5-nCoV in preventing symptomatic, PCR-confirmed COVID-19 infection occurring at least 28 days after vaccination in all participants who were at least 28 days postvaccination on Jan 15, 2021. The primary safety objective evaluated the incidence of any serious adverse events or medically attended adverse events postvaccination in all participants who received a study injection. This trial is closed for enrolment and is registered with ClinicalTrials.gov (NCT04526990). FINDINGS: Study enrolment began on Sept 22, 2020, in Pakistan, Nov 6, 2020, in Mexico, Dec 2, 2020, in Russia and Chile, and Dec 17, 2020, in Argentina; 150 endpoint cases were reached on Jan 15, 2021, triggering the final primary efficacy analysis. One dose of Ad5-nCoV showed a 57·5% (95% CI 39·7-70·0, p=0·0026) efficacy against symptomatic, PCR-confirmed, COVID-19 infection at 28 days or more postvaccination (21 250 participants; 45 days median duration of follow-up [IQR 36-58]). In the primary safety analysis undertaken at the time of the efficacy analysis (36 717 participants), there was no significant difference in the incidence of serious adverse events (14 [0·1%] of 18 363 Ad5-nCoV recipients and 10 [0·1%] of 18 354 placebo recipients, p=0·54) or medically attended adverse events (442 [2·4%] of 18 363 Ad5-nCoV recipients and 411 [2·2%] of 18 354 placebo recipients, p=0·30) between the Ad5-nCoV or placebo groups, or any serious adverse events considered related to the study product (none in both Ad5-nCoV and placebo recipients). In the extended safety cohort, 1004 (63·5%) of 1582 of Ad5-nCoV recipients and 729 (46·4%) of 1572 placebo recipients reported a solicited systemic adverse event (p<0·0001), of which headache was the most common (699 [44%] of Ad5-nCoV recipients and 481 [30·6%] of placebo recipients; p<0·0001). 971 (61·3%) of 1584 Ad5-nCoV recipients and 314 (20·0%) of 1573 placebo recipients reported an injection-site adverse event (p<0·0001), of which pain at the injection site was the most frequent; reported by 939 (59%) Ad5-nCoV recipients and 303 (19%) placebo recipients. INTERPRETATION: One dose of Ad5-nCoV is efficacious and safe in healthy adults aged 18 years and older. FUNDING: CanSino Biologics and the Beijing Institute of Biotechnology.
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Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/diagnóstico , COVID-19/imunologia , COVID-19/virologia , Teste de Ácido Nucleico para COVID-19/estatística & dados numéricos , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Imunogenicidade da Vacina , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/genética , SARS-CoV-2/imunologia , Vacinação/métodos , Adulto JovemRESUMO
BACKGROUND: Lung cancer is the most common cause of cancer-related death globally. There are several reasons for this high mortality rate, including metastasis to multiple organs, especially the brain. Exosomes play a pivotal role in tumor metastasis by remodeling the microenvironment of remote target organs and promoting the pre-metastatic niche's formation. Since astrocytes are indispensable for maintaining the homeostasis of brain microenvironment, it's of great interest to explore the influence of lung cancer cell-derived exosomes on astrocytes to further understand the mechanism of lung cancer brain metastasis. RESULTS: Twenty four h after co-culture of H1299 cell-derived exosomes and SVG P12 cells, the viability of astrocytes decreased and the apoptosis increased. The levels of cytokines in the supernatant including GROα/CXCL1, IFN-γ, IL-3, IL-5, IL-15, LIF, M-CSF, NGF, PDGF, and VEGF were significantly enhanced, while IL-7 secretion was significantly reduced. Meanwhile, apoptosis-related proteins MAP2K1, TUBA1C, RELA, and CASP6 were up-regulated. And the differentially expressed proteins were involved in regulating metabolic pathways. CONCLUSION: Exosomes of H1299 could induce apoptosis of astrocytes as well as promote their secretion of cytokines that were conducive to the formation of the inflammatory microenvironment and immunosuppressive microenvironment, and affect their metabolic pathways, thus facilitating the formation of pre-metastatic niche in lung cancer brain metastases.
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The layered ternary CuSbSe2 semiconductor with ultralow thermal conductivity is particularly suitable for thermoelectric applications. Nevertheless, its poor electrical conductivity greatly lowers the dimensionless figure of merit ZT and accordingly limits its thermoelectric applications. Here, we use first-principles calculations combined with semi-classical Boltzmann transport theory to evaluate the thermoelectric properties of MO-intercalated (M = Mg, Ca, Sr, and Ba) CuSbSe2. Compared with CuSbSe2, MO-intercalated CuSbSe2 semiconductors, as a new class of semiconductors, host distorted lattices with low symmetry monoclinic structures. Such a structure feature provides desired channels for electron transport between adjacent layers and accordingly enhances electrical transport properties. Meanwhile, the MO intercalation effectively softens phonons and gives rise to an ultralow lattice thermal conductivity in MOCuSbSe2. These synergistically yield a high figure of merit ZT of â¼4.17 for MgO-intercalated CuSbSe2 at 200 K with electron doping being n = 1018 cm-3. Our study provides an effective route to improve the thermoelectric performance of layered CuSbSe2 by designing new multicomponent thermoelectric compounds with alternatively stacked [CuSbSe2] (electronic conduction units) and [MO] (electronic insulation units) layers. The approach can be extended to similar chalcostibite compounds for screening and designing thermoelectric materials.
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The application of a bidirectional laser requires the laser intensity in both directions to be balanced. However, the CW and CCW light intensities in current bidirectional erbium-doped fiber laser experiments differ due to the gain competition effect. There is no report on equalizing the intensity in the CW and CCW directions. This paper proposes a bidirectional non-reciprocal optical attenuator using the Faraday optical rotation effect. Continuous attenuation adjustment is realized by changing the angle between the polarizer's transmission axis and the linear polarized light. In this study, we analyzed the influence of different parameters on the device's performance, built a non-reciprocal attenuator, and tested the bidirectional attenuation curve, which was consistent with the simulation results. The device was integrated into a bidirectional fiber laser, and the light intensity in both directions was balanced through non-reciprocal adjustment. Combined with closed-loop control, the average intensity difference fluctuation between the two directions was controlled at 0.28% relative to the average power, realizing stable long-term bidirectional fiber laser intensity equalization.
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Utilizing the difference in phase and power spectrum between signals and noise, the estimation of direction of arrival (DOA) can be transferred to a spatial sample classification problem. The power ratio, namely signal-to-noise ratio (SNR), is highly required in most high-resolution beamforming methods so that high resolution and robustness are incompatible in a noisy background. Therefore, this paper proposes a Subspaces Deconvolution Vector (SDV) beamforming method to improve the robustness of a high-resolution DOA estimation. In a noisy environment, to handle the difficulty in separating signals from noise, we intend to initial beamforming value presets by incoherent eigenvalue in the frequency domain. The high resolution in the frequency domain guarantees the stability of the beamforming. By combining the robustness of conventional beamforming, the proposed method makes use of the subspace deconvolution vector to build a high-resolution beamforming process. The SDV method is aimed to obtain unitary frequency matrixes more stably and improve the accuracy of signal subspaces. The results of simulations and experiments show that when the input SNR is less than -27 dB, signals of decomposition differ unremarkably in the subspace while the SDV method can still obtain clear angles. In a marine background, this method works well in separating the noise and recruiting the characteristics of the signal into the DOA for subsequent processing.
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Algoritmos , Ruído , Razão Sinal-RuídoRESUMO
Frequency-modulated (FM) signals are widely used in sensing, measurement, and signal detection due to their strong anti-interference and easy transmission characteristics. Although the high-precision measurement methods for static signals are quite complete, the high-precision measurement methods for dynamic FM signals still need to be studied, and the measurement accuracy in the high-sampling system still has room for improvement. Traditionally, the equal-precision measurement method is widely applied in most scenarios. However, its accuracy is limited by the quantization error of ±1 word and the sampling gate time, making it difficult to improve the frequency measurement accuracy while ensuring a high sampling rate at the same time. In this paper, a high-precision feedback frequency measurement system with the capability to eliminate the quantization error of ±1 word is proposed. The proposed system consists of two stages, the rough measurement stage based on the equal-precision measurement method and the precise measurement stage based on the negative feedback tracking architecture using the phase-frequency detector (PFD) and direct digital synthesizer (DDS). The effectiveness and feasibility of the system are verified by both simulation and experiment. At the sampling rate of 2 kHz, the frequency measurement accuracy is improved by more than 30 dB.
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Simulação por Computador , RetroalimentaçãoRESUMO
Electrostatic suspended accelerometers (ESAs) are widely used in high accuracy acceleration measurement. However, there exist accumulated charges on the isolated mass which damage the accuracy and the stability of ESAs. In this paper, we propose to apply actuation voltage with a combined waveform to suppress the acceleration noise due to deposited charge. A model of the electrostatic force on the mass is established and the deviation voltage is found to be the dominant source of charge noise. Based on the analysis of disturbance electrostatic force under DC and AC signals, actuation combined with DC and AC voltage is designed and the disturbance force due to charge can be suppressed through adjustment towards the duty cycle of different compositions. Simulations and experiments are carried out and the results indicate that the disturbance due to charge can be suppressed up to 40%, which validates the efficiency of the scheme.
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Source localization with a passive sensors array is a common topic in various areas. Among the popular source localization algorithms, the compressive sensing (CS)-based method has recently drawn considerable interest because it is a high-resolution method, robust with coherent sources and few snapshots, and applicable for mixed near-field and far-field source localization. However, the CS-based methods rely on the dense grid to ensure the required estimation precision, which is time-consuming and impractical. This paper applies the complex variational mode decomposition (CVMD) to source localization. Specifically, the signal model of the source localization problem is similar to the time-domain frequency-modulated signal model. Motivated by this, we extend CVMD, initially designed for nonstationary time-domain signal analysis, to array signal processing. The decomposition results of the array measurements can correspond to the potential sources at different locations. Then, the sources' direction and range can be estimated by model fitting with the decomposed subsignals. The simulation results show that the proposed CVMD-based method can locate the pure far-field, pure near-field, mixed far-field, and near-field sources. Notably, it can yield high-resolution localization for the coherent sources with one single snapshot with low computing time.
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Underwater target detection and identification technology are currently two of the most important research directions in the information disciplines. Traditionally, underwater target detection technology has struggled to meet the needs of current engineering. However, due to the large manifold error of the underwater sonar array and the complexity of ensuring long-term signal stability, traditional high-resolution array signal processing methods are not ideal for practical underwater applications. In conventional beamforming methods, when the signal-to-noise ratio is lower than -43.05 dB, the general direction can only be vaguely identified in the general direction. To address the above challenges, this paper proposes a beamforming method based on a deep neural network. Through preprocessing, the space-time domain of the target sound signal is converted into two-dimensional data in the angle-time domain. Subsequently, we trained the network with enough sample datasets. Finally, high-resolution recognition and prediction of two-dimensional images are realized. The results of the test dataset in this paper demonstrate the effectiveness of the proposed method, with a minimum signal-to-noise ratio of -48 dB.
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Redes Neurais de Computação , Som , Processamento de Sinais Assistido por Computador , Razão Sinal-RuídoRESUMO
PURPOSE OF REVIEW: Despite the significant advances in EGFR-mutant nonsmall cell lung cancer (NSCLC), some challenges remain. One of the permanent and inevitable issues is the emergence of acquired resistance. Therefore, blocking the activation of EGFR pathway and overcoming drug resistance with novel agents are still in high demand. Here, we review the development of novel drugs in EGFR-mutant, advanced NSCLC, including targeting EGFR exon 20 insertion (EGFR20ins), and novel role of epidermal growth factor receptor, tyrosine kinase inhibitor (EGFR-TKIs) in early-stage NSCLC. RECENT FINDINGS: EGFR-TKIs as adjuvant therapy or neoadjuvant therapy in patients with early-stage NSCLC with EGFR-sensitizing mutations have shown promising efficacy. The resistance mechanisms of third-generation EGFR-TKIs can be divided into two types: EGFR dependent and EGFR independent. Several clinical trials have demonstrated that the addition of MET inhibitors to EGFR-TKIs was an effective option for patients who had acquired resistance to EGFR-TKIs caused by hepatocyte growth factor receptor gene (MET) amplification or overexpression. Novel compounds that selectively and potently inhibit EGFR20ins are being investigated in phase III studies. SUMMARY: A better characterization and understanding of resistance mechanisms to first-line osimertinib and adjuvant osimertinib is helpful to guide further treatment.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/genética , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Mutação , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Brain metastasis is an important cause of increased mortality in patients with non-small cell lung cancer (NSCLC). In brain metastasis, the blood-brain barrier (BBB) is frequently impaired, forming blood-tumor barrier (BTB). The efficacy of chemotherapy is usually very poor. However, the characteristics of BTB and the impacts of BTB on chemotherapeutic drug delivery remain unclear. The present study investigated the structure of BTB, as well as the distribution of routine clinical chemotherapeutic drugs in both brain and peripheral tumors. METHODS: Bioluminescent image was used to monitor the tumor load after intracranial injection of lung cancer Lewis cells in mice. The permeability of BBB and BTB was measured by fluorescent tracers of evans blue and fluorescein sodium. Transmission electron microscopy (TEM), immunohistochemistry and immunofluorescence were performed to analyze structural differences between BBB and BTB. The concentrations of chemotherapeutic drugs (gemcitabine, paclitaxel and pemetrexed) in tissues were assayed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). RESULTS: Brain metastases exhibited increased BTB permeability compared with normal BBB detected by fluorescence tracers. TEM showed abnormal blood vessels, damaged endothelial cells, thick basement membranes, impaired intercellular endothelial tight junctions, as well as increased fenestrae and pinocytotic vesicles in metastatic lesions. Immunohistochemistry and immunofluorescence revealed that astrocytes were distributed surrounded the blood vessels both in normal brain and the tumor border, but no astrocytes were found in the inner metastatic lesions. By LC-MS/MS analysis, gemcitabine showed higher permeability in brain metastases. CONCLUSIONS: Brain metastases of lung cancer disrupted the structure of BBB, and this disruption was heterogeneous. Chemotherapeutic drugs can cross the BTB of brain metastases of lung cancer but have difficulty crossing the normal BBB. Among the three commonly used chemotherapy drugs, gemcitabine has the highest distribution in brain metastases. The permeability of chemotherapeutic agents is related to their molecular weight and liposolubility.
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Two-dimensional vanadium pentoxide inverse opal (2D V2O5IO) architecture was fabricated by polystyrene (PS) sphere template assisted electrodeposition process. In comparison to the un-templated V2O5film, the 2D V2O5IO film exhibited a highly ordered hexagonal close-packed bowel-like array, as well as noticeable electrochromism, such as transmittance modulation up to 42.6% at 800 nm, high coloration efficiency (28.6 cm2 · C-1), fast ions transfer kinetic (tb = 7.2 s,tc = 2.5 s). These improvements of electrochromic performance were attributed to the ordered morphology with larger surface areas, which considerably shortened the ions diffusion paths and accelerated ions migration. An electrochromic energy storage device assembled from the 2D V2O5IO film with simultaneous electrochromic and pseudocapacitive performance could not only show transmittance modulation accompanied by multicolor variations but also powered an LCD screen and an LED bulb, demonstrating a promising potential for practical applications.
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Emergency vaccination programs often are needed to control outbreaks of meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) on college campuses. Such campaigns expend multiple campus and public health resources. We conducted a randomized, controlled, multicenter, observer-blinded trial comparing immunogenicity and tolerability of an accelerated vaccine schedule of 0 and 21 days to a longer interval of 0 and 60 days for 4-component MenB vaccine (MenB-4C) in students 17-25 years of age. At day 21 after the first MenB-4C dose, we observed protective human serum bactericidal titers >4 to MenB strains 5/99, H44/76, and NZ 98/254 in 98%-100% of participants. Geometric mean titers increased >22-fold over baseline. At day 180, >95% of participants sustained protective titers regardless of their vaccine schedule. The most common adverse event was injection site pain. An accelerated MenB-4C immunization schedule could be considered for rapid control of campus outbreaks.
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Surtos de Doenças/prevenção & controle , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/administração & dosagem , Neisseria meningitidis Sorogrupo B/imunologia , Estudantes , Adolescente , Serviços de Saúde do Adolescente , Adulto , Canadá/epidemiologia , Método Duplo-Cego , Feminino , Humanos , Esquemas de Imunização , Masculino , Universidades , Vacinação , Adulto JovemRESUMO
Immunotherapy has become a hotspot in cancer therapy in recent years. Several immune checkpoints inhibitors have been used to treat lung cancer. CD137 is a kind of costimulatory molecule that mediates T cell activation, which regulates the activity of immune cells in a variety of physiological and pathological processes. Targeting CD137 or its ligand (CD137L) has been studied, aiming to enhance anticancer immune responses. Accumulating studies show that anti-CD137 mAbs alone or combined with other drugs have bright antitumor prospects. In the following, we reviewed the biology of CD137, the antitumor effects of anti-CD137 Ab monotherapy and the combined therapy in lung cancer.
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Anticorpos Monoclonais/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imunoterapia , Neoplasias Pulmonares/terapia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Animais , Anticorpos Monoclonais/imunologia , Terapia Combinada , Humanos , Fatores Imunológicos/imunologia , Neoplasias Pulmonares/imunologia , Ativação Linfocitária , Transdução de Sinais/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
Interferometric fiber-optic hydrophones are an important means in the field of underwater acoustic detection. The design of the hydrophone sensor head is the key technology related to its detection sensitivity. In this paper, a high-sensitivity cuboid interferometric fiber-optic hydrophone based on planar rectangular film sensing is proposed, and the sensitivity of the sensor is compared with that of the widely used air-backed mandrel hydrophone under the same conditions. The acoustic characteristic models of the two types of sensors were established by theoretical calculation and simulation analysis to obtain the theoretical pressure sensitivity. Some experiments were performed to examine the theory and design. According to the experiment results, the mean phase sensitivity of the mandrel type was -112.85 dB re 1 rad/µPa in the operating frequency range of 10-300 Hz, and that of the cuboid type was -84.50 dB re 1 rad/µPa. The latter was 28.35 dB higher than the former was. These results are useful for improving hydrophone sensitivity.
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Dead time estimation is important in the design process of quartz flexure accelerometers. However, to the authors' knowledge, the dead time existing in quartz flexure accelerometers is not well investigated in conventional identification studies. In this paper, the dead time, together with the open-loop transfer function of quartz flexure accelerometers, is identified from step excitation experiments using two steps. Firstly, a monotonicity number was proposed to estimate the dead time. Analysis showed that the monotonicity number was robust enough to measurement noise and sensitive to step excitation. Secondly, parameters of the open-loop transfer function were identified using the least mean squares algorithm. A simulation example was applied to demonstrate the validity of the proposed method. The verified method was used to test a quartz flexure accelerometer. The experimental result shows that the dead time was 500 µs.
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Background: Respiratory syncytial virus infection can cause lower respiratory tract infection in older adults comparable to influenza, but no vaccines are available. Methods: This was a randomized, observer-blinded, first-in-humans study of a novel synthetic RSV antigen based on the ectodomain of the small hydrophobic glycoprotein (SHe) of RSV subgroup A, formulated with either the lipid and oil-based vaccine platform DepoVax (DPX-RSV[A]) or alum (RSV[A]-Alum), in healthy, 50-64-year-old individuals. Two dose levels (10 or 25 µg) of SHe with each formulation were compared to placebo. A booster dose was administered on day 56. Results: There was no indication that the vaccine was unsafe. Mild pain, drowsiness, and muscles aches were the most common solicited adverse events (AEs), and the frequencies of the AEs did not increase after dose 2. Robust anti-SHe-specific immune responses were demonstrated in the DPX-RSV(A) 10-µg and 25-µg groups (geometric mean titer, approximately 10-fold and 100-fold greater than that of placebo at days 56 and 236, respectively), and responses were sustained in the DPX-RSV(A) 25-µg group at day 421. Responses to the RSV(A)-Alum vaccines were very low. Conclusions: A novel antigen from the SH protein of RSV, formulated in a lipid and oil-based vaccine platform, was highly immunogenic, with sustained antigen-specific antibody responses, and had an acceptable safety profile.
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Adjuvantes Imunológicos/administração & dosagem , Anticorpos Antivirais/sangue , Lipídeos/administração & dosagem , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Proteínas Oncogênicas de Retroviridae/imunologia , Compostos de Alúmen/administração & dosagem , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Voluntários Saudáveis , Humanos , Imunidade Humoral , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Método Simples-Cego , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/efeitos adversos , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
Background: Immunization of pregnant women with tetanus-diphtheria-acellular pertussis vaccine (Tdap) provides protection against pertussis to the newborn infant. Methods: In a randomized, controlled, observer-blind, multicenter clinical trial, we measured the safety and immunogenicity of Tdap during pregnancy and the effect on the infant's immune response to primary vaccination at 2, 4, and 6 months and booster vaccination at 12 months of age. A total of 273 women received either Tdap or tetanus-diphtheria (Td) vaccine in the third trimester and provided information for the safety analysis and samples for the immunogenicity analyses; 261 infants provided serum for the immunogenicity analyses. Results: Rates of adverse events were similar in both groups. Infants of Tdap recipients had cord blood levels that were 21% higher than maternal levels for pertussis toxoid (PT), 13% higher for filamentous hemagglutinin (FHA), 4% higher for pertactin (PRN), and 7% higher for fimbriae (FIM). These infants had significantly higher PT antibody levels at birth and at 2 months and significantly higher FHA, PRN, and FIM antibodies at birth and 2 and 4 months, but significantly lower PT and FHA antibody levels at 6 and 7 months and significantly lower PRN and FIM antibody levels at 7 months than infants whose mothers received Td. Differences persisted prebooster at 12 months for all antigens and postbooster 1 month later for PT, FHA, and FIM. Conclusions: This study demonstrated that Tdap during pregnancy results in higher levels of antibodies early in infancy but lower levels after the primary vaccine series. Clinical Trials Registration: NCT00553228.