Study population
This is an observational cross-sectional investigation comparing two cohorts of vaccinees defined by vaccine dosage (fractional and standard doses) carried out in the metropolitan area of So Paulo (SP, Brazil) by the Collaborative Group for Studies of Yellow Fever Vaccine. The study protocol was submitted and approved by research ethics committees at Instituto Ren RachouFundao Oswaldo Cruz (CAAE: 82357718.5.0000.5091), Instituto Nacional de Infectologia Evandro Chagas/INIFundao Oswaldo Cruz (CAAE: 82357718.5.3001.5262), Secretaria Municipal da Sade de So Paulo - SMS/SP (CAAE: 82357718.5.3003.0086) and Instituto de Infectologia Emlio RibasIIER (CAAE: 82357718.5.3002.0061). The study population comprised a non-probabilistic convenience sampling including whole blood specimens (n=322 samples) collected from healthy subjects of both genders (Males=142 samples; Females=180 samples), with age ranging from 11 to 65years (Mean=4114), further categorized into two groups referred as Fractional Dose (FD) and Standard Dose (SD). Written informed consent was given from all participants that have joined this study. Only volunteers with negative results of YF-specific neutralizing antibodies prior to vaccination were enrolled in the present study.
The FD group was enrolled between January and July 2018 at primary care medical centers, during the large-scale vaccination campaign with the fractional dose (1/5 of SD) of the 17DD-YF vaccine in three cities at the metropolitan area of So Paulo (Diadema, Mau and Santo Andr). This group included 225 samples (Males=99; Females=126), with age ranging from 11 to 65years (Mean=4314).
Between April and August 2019, the SD group was selected during the routine 17DD-YF vaccination at primary care medical centers in So Paulo. This group included 97 samples (Males=44; Females=53), aged 1763years (Mean=3512).
Blood samples (10mL) were collected at baseline (D0) and at distinct timepoints after primary 17DD-YF vaccination (from D1 throughout D15 and at D30-45) by venipuncture using a gel separation vacuum system without anticoagulant. Aiming to assess the kinetics timeline of distinct parameters, categorical day intervals were defined by grouping D1 to D15 depending on the number of samples available.
Blood specimens were processed to obtain serum samples and peripheral blood mononuclear cells (PBMC) as previously described by Reis et al.30. Whole blood samples were submitted to centrifugation at 10002000g for 10min at room temperature to obtain serum samples, and aliquots stored at 80C at Laboratrio de Investigao Mdica from Universidade de So Paulo (USP) for further viremia quantification, YF-specific IgM, IgG and neutralizing antibodies detection, as well as analysis of soluble mediators. Clots were processed at Laboratrio de Biomarcadores from Instituto Ren Rachou (IRR, FIOCRUZ-Minas) for PBMC isolation. Clots were removed from the gel separation system, sliced into 12mm fragments, and minced with sterile syringe plungers through 100m filters attached to 50mL conical tubes containing RPMI-1640 medium and resuspended with RPMI supplemented with 10% Fetal Bovine Serum to obtain a final volume of 10mL. The suspension was slowly applied over 5mL Ficoll-Paque PLUS cushion (1077g/mL) and submitted to centrifugation at 410g for 40min at room temperature. PBMC were transferred to 50mL conical tubes and washed once with 15mL supplemented RPMI-1640 medium by centrifugation at 300g for 7min at 4C. Thereafter, the supernatant was discarded and the cell pellet was treated with ammonium chloride solution (155mM NH4Cl, 10mM KHCO3, 0.1mM EDTA, pH 7.2) for 10min at room temperature to lyse the remaining red blood cells. Following centrifugation at 300g for 7min at 4C, the PBMC pellet was washed once with RPMI-1640 and resuspended in 1mL. Aliquots of 10L were stained with Trypan Blue (0.4%) to estimate cell viability using the Countess Automated Cell Counter. PBMC suspensions were maintained at 4C for further use for immunophenotyping staining.
The quantification of YF viral copies in serum samples collected from D3 throughout D15 after primary immunization with SD or FD of 17DD-YF vaccine was performed through Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) at Laboratrio de Tecnologia Virolgica in Bio-Manguinhos (LATEV, FIOCRUZ), as previously described by Martins et al.15. The limit of detection (LOD) of the test was obtained through the validation process of the one step qPCR assay for yellow fever carried out in Bio-Manguinhos. LOD: 6.25 copies/L or 3.45 Log10 copies/mL. The results were expressed as viral copies/mL according to the standard curve included in each experimental batch.
The quantification of Anti-YF IgM was performed at the Laboratrio de Tecnologia Imunolgica from Bio-Manguinhos (LATIM, FIOCRUZ) using a standardized in-house capture enzyme-linked immunosorbent assay (ELISA). Briefly, 96-well plates were coated with 75L/well of anti-IgM antibody (10g/mL) in carbonate-bicarbonate buffer, pH 9.6, and incubated overnight at 4C in a humid chamber. Following incubation, the supernatant was discarded and plates were incubated with 200 L/well of blocking solution [BDS1, prepared as phosphate-buffered saline (PBS), pH 7.2, supplemented with 0.5% Tween-20 (PBS/T1) supplemented and 5% skimmed milk] for 30min in a humid chamber at room temperature (RT). After 5 times washing with PBS/T1, 50 L of pre-diluted serum samples and controls (1:200) in PBS/T1 were added together with 50L/well of 17DD-YF live-attenuated virus (2g/mL). The viral antigen concentration was previously determined during standardization steps using distinct protein concentrations measured by BCA protein assay kit (Pierce), according to the manufacturers instructions. The plate was incubated overnight at 4C in a humid chamber, following washing steps, and 50L/well of commercially available anti-Flavivirus antibody (6B6C-1) conjugated with Horseradish Peroxidase was added to each well for 1h at 37C. After washing steps, 75L/well of 3,3,5,5-tetramethylbenzidine substrate solution (TMB) was added to each well and plates were incubated for 10min before addition of 50 L/well of stop-solution (2M H2SO4). The endpoint measurements were performed at 450nm. The optical density (OD) values of each sample were subtracted from the negative control. The results were considered positive at OD>0.800, borderline at OD ranging from 0.800 to 0.667 and negative at OD<0.667.
The quantification of Anti-YF IgG was performed at the Laboratrio de Tecnologia Imunolgica from Bio-Manguinhos (LATIM, FIOCRUZ) using a standardized in-house enzyme-linked immunosorbent assay (ELISA). Briefly, 96-well plates were coated with 50 L/well of 17DD-YF live-attenuated virus (2.5g/mL) in carbonate-bicarbonate buffer, pH 9.6. The viral antigen concentration was previously determined during standardization steps using distinct protein concentrations measured by BCA protein assay kit (Pierce), according to the manufacturers instructions. The microplates were incubated overnight at 4C in a humid chamber and were mechanically washed 5 times with 300 L/well of phosphate-buffered saline (PBS) pH 7.4, supplemented with 0.05% Tween-20 (PBS/T2). The plates were incubated with 100L/well of blocking solution [BDS2, prepared as PBS/T2 supplemented with 0.05% bovine serum albumin (BSA), 3% fetal bovine serum (FBS) and 5% skimmed milk], for 1h at 37C. Following, 50 L of two-fold serial dilution of serum samples (1:20 to 1:160) in BDS2 were incubated for 1h at RT. The standard curve was constructed using two-fold serial dilution (10.015 UI/mL) of commercially available anti-YF serum (YFNIBSC). After incubation, plates were washed and reincubated with 100 L/well of anti-Human IgG conjugated with Horseradish Peroxidase (HRP, BD Biosciences) diluted 1:3.000 in BDS2 for 1h at RT. Following washing procedures, 100L/well of TMB solution was added to each well and the plates were incubated for 15min before addition of 100L/well of stop-solution (2M H2SO4). The endpoint measurements were performed at 450nm. The absorbances of the serum sample dilutions were plotted and the standard curve was used to determine the antibody concentration according to the 4-parameter logistic regression, using the software SoftMax Pro. The results were expressed in IU/mL relative to the reference anti-YF serum standard curve.
The analysis of YF-specific neutralizing antibodies was performed at the Laboratrio de Tecnologia Virolgica at Bio-Manguinhos (LATEV, FIOCRUZ) using the micro plaque-reduction neutralizationHorseradish Peroxidase test (PRN-HRP), according to Simes M.67. Briefly, in 96-well plates, serial dilutions of serum samples (1:61:1458) were pre-incubated with 17D-213/77 vaccine virus (~100 PFU/well) for 2h at 37C, 5% CO2, and transferred to pre-formed Vero cells monolayer. Carboxymethylcellulose semisolid medium was overlaid on each well and plates were incubated for 48h at 37C, 5% CO2. After incubation, cell monolayers were washed and fixed with ethanol/methanol (1:1) solution and incubated with HRP-conjugated monoclonal antibody (clone 4G2) for 2h at 35C, 5% CO2, followed by the addition of True Blue Dye substrate. Thereafter, monolayers were washed, dried and photographed using the ScanLab microscope and images were used for the automated counts. The endpoint-neutralizing antibody titers were defined as the last serum dilution that reduced the number of plaques by 50% (PRN-HRP50) as compared to the virus control included in each assay. Seropositivity was defined considering the antibody titer 100 as the cut-off.
High-performance microbead array (Bio-Plex ProTM Human Assay) was used to quantify serum soluble mediators, comprising: chemokines (CCL11, CXCL8, CCL2, CCL3, CCL4, CCL5 and CXCL10), cytokines (IL-1, IL-6, TNF, IL-12, IFN-, IL-17, IL-1Ra, IL- 4, IL-5, IL-9, IL-10 and IL-13) and growth factors (FGF, PDGF, VEGF, G-CSF, IL-2 and IL-7). The assays were performed according to the manufacturers instructions. The results were expressed in pg/mL according to the standard curve of each soluble factor.
Immunophenotyping of T and B-cell subpopulations was performed in 96-well plates by incubating 5 105 live PBMC with two panels of monoclonal antibodies. The T-cell panel included anti-CD3-Qdot655 (Invitrogen, clone S4.1, dilution: 0.12:100, Cat #: Q10012), anti-CD4-BV605 (BD, clone RPA-T4, dilution: 1:100, Cat #: 562658), anti-CD8-Alexa Fluor 700 (eBioscience, clone RPA-T8, dilution: 5:100, Cat #: 56-0088-42), anti-CD45RO-BV421 (BD, clone UCHL1, dilution: 1:100, Cat #: 562641), anti-CD27-APC-H7 (BD, clone M-T271, dilution: 5:100, Cat #: 560222), anti-CXCR5-Alexa Fluor 488 (BD, clone RF8B2, dilution: 5:100, Cat #: 558112), anti-CXCR3-PE (BD, clone 1C6, dilution: 5:100, Cat #: 557185), anti-CCR6-PerCP-Cy5.5 (BD, clone 11A9, dilution: 5:100, Cat #: 560467), anti-ICOS-PE-Cy7 (Invitrogen, clone ISA-3, dilution: 5:100, Cat #: 25-9948-42) and anti-PD-1-APC (BioLegend, clone EH12.2H7, dilution: 5:100, Cat #: 329908). The B-cell panel comprised anti-CD19-PE-Cy7 (eBioscience, clone: SJ25C1, dilution: 0.20:100, Cat #: 25-0198-42), anti-CD20-BV650 (BD, clone 2H7, dilution: 2:100, Cat #: 563780), anti-CD21-FITC (eBioscience, clone HB5, dilution: 1.25:100, Cat #: 11-0219-42), anti-CD38- PE (BD, clone HIT2, dilution: 2.5:100, Cat #: 555460), anti-CD27-APC-H7 (BD, clone M-T271, dilution: 2.5:100, Cat #: 560222), and anti-IgD-Alexa Fluor 700 (BD, clone IA6-2, dilution: 2.5:100, Cat #: 561302). Cells were incubated for 20min at room temperature, washed and resuspended in PBS prior to acquisition on a LSR Fortessa Flow Cytometer (BD Biosciences). The FlowJo V10.8.1 (BD Bioscience) software was employed for data analysis using distinct gating strategies. Lymphocytes were selected based on the size and granularity properties within gated single cells. Thereafter, CD4+ and CD8+ T-cell subsets selected amongst CD3+ T cells were further characterized by additional phenotypic features. B-cell were identified as CD19+ cells within CD3- followed by further additional phenotypic analysis of cell subsets.
The GraphPad Prism V8.0 (GraphPad-Software) was used for statistical analyses and graphical arts. Data normality distribution was assessed by the Shapiro-Wilk test. MannWhitney test or Student t-test were used for comparison between two groups. KruskalWallis or ANOVA variance analysis followed by Dunns or Tukey post-test were employed for multiple comparisons. In all cases, significance was considered at p<0.05.
The baseline fold change indices were calculated as the ratio between the results observed for individual samples at distinct timepoints after primary 17DD-YF vaccination divided by the baseline values obtained for the same volunteer before vaccination. Chi-square test was used for the comparison of baseline fold changes categorized as decreased (<1), unaltered (=1) or increased (>1). Significance was considered at p<0.05. Venn Diagram analysis, available at (http://bioinformatics.psb.ugent.be/webtools/Venn/), was employed to assess the common and selective serum soluble mediators with increased (>1.5) or decreased (<0.5) baseline fold-change profiles at distinct timepoints.
Correlation analyses were carried out using Pearson and Spearman rank tests. The r scores of significant correlations (p<0.05) were employed to build correlation matrices and to assemble networks, using the corrplot package of the R software (Project for Statistical Computing Version 3.0.1) and the open-source Cytoscape software platform (available at https://cytoscape.org), respectively. Networks were compiled to arrange clusters of antibodies, chemokines, cytokines, growth factors, T and B-cell subsets. Nodes were used to represent each parameter and connecting lines were employed to identify positive (continuous line) and negative (dashed line) correlations. The node sizes are proportional to the number of correlations between parameters. Line thickness illustrates the correlation strength, ranging from weak/moderate (r scores from 0.1 to 0.5 or 0.5 to 0.1, thin lines) to strong correlations (r scores from 0.5 or0.5, thick lines).
Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Bagcchi, S. WHOs global tuberculosis report 2022. Lancet Microbe 4, e20 (2023).
Article Google Scholar
Di Gennaro, F. et al. Increase in tuberculosis diagnostic delay during first wave of the COVID-19 pandemic: data from an Italian Infectious Disease Referral Hospital. Antibiotics 10, 272 (2021).
Article PubMed Central Google Scholar
Comella-Del-Barrio, P., De Souza-Galvao, M. L., Prat-Aymerich, C. & Dominguez, J. Impact of COVID-19 on tuberculosis control. Arch. Bronconeumol. 57, 56 (2021).
Article Google Scholar
Excler, J. L., Saville, M., Berkley, S. & Kim, J. H. Vaccine development for emerging infectious diseases. Nat. Med. 27, 591600 (2021).
Article CAS Google Scholar
World Health, O. BCG vaccine: WHO position paper, February 2018 - Recommendations. Vaccine 36, 34083410 (2018).
Article Google Scholar
Lobo, N. et al. 100 years of Bacillus Calmette-Guerin immunotherapy: from cattle to COVID-19. Nat. Rev. Urol. 18, 611622 (2021).
Article CAS PubMed Central Google Scholar
Bellini, C. & Horvati, K. Recent advances in the development of protein- and peptide-based subunit vaccines against tuberculosis. Cells 9, 2673 (2020).
Article CAS PubMed Central Google Scholar
Tait, D. R. et al. Final analysis of a trial of M72/AS01(E) vaccine to prevent tuberculosis. N. Engl. J. Med. 381, 24292439 (2019).
Article CAS Google Scholar
Nemes, E. et al. Prevention of M. tuberculosis infection with H4:IC31 vaccine or BCG revaccination. N. Engl. J. Med. 379, 138149 (2018).
Article CAS PubMed Central Google Scholar
Choi, Y. H. et al. Safety and immunogenicity of the ID93 + GLA-SE tuberculosis vaccine in BCG-vaccinated healthy adults: a randomized, double-blind, placebo-controlled phase 2 trial. Infect. Dis. Ther. 12, 16051624 (2023).
Article PubMed Central Google Scholar
Dijkman, K. et al. A protective, single-visit TB vaccination regimen by co-administration of a subunit vaccine with BCG. NPJ Vaccines 8, 66 (2023).
Article CAS PubMed Central Google Scholar
Singh, S., Saraav, I. & Sharma, S. Immunogenic potential of latency associated antigens against Mycobacterium tuberculosis. Vaccine 32, 712716 (2014).
Article CAS Google Scholar
Kaufmann, S. H. The contribution of immunology to the rational design of novel antibacterial vaccines. Nat. Rev. Microbiol. 5, 491504 (2007).
Article CAS Google Scholar
Day, T. A. et al. Safety and immunogenicity of the adjunct therapeutic vaccine ID93 + GLA-SE in adults who have completed treatment for tuberculosis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet Respir. Med. 9, 373386 (2021).
Article CAS Google Scholar
Suliman, S. et al. Dose optimization of H56:IC31 vaccine for tuberculosis-endemic populations. A double-blind, placebo-controlled, dose-selection trial. Am. J. Respir. Crit. Care Med. 199, 220231 (2019).
Article CAS Google Scholar
Didierlaurent, A. M. et al. Adjuvant system AS01: helping to overcome the challenges of modern vaccines. Expert Rev. Vaccines 16, 5563 (2017).
Article CAS Google Scholar
Ko, A. et al. Comparison of the adjuvanticity of two adjuvant formulations containing de-O-acylated lipooligosaccharide on Japanese encephalitis vaccine in mice. Arch. Pharm. Res. 41, 219228 (2018).
Article CAS Google Scholar
Ko, A. et al. Potentiation of Th1-type immune responses to Mycobacterium tuberculosis antigens in mice by cationic liposomes combined with de-O-acylated lipooligosaccharide. J. Microbiol. Biotechnol. 28, 136144 (2018).
Article CAS Google Scholar
Wui, S. R. et al. Efficient induction of cell-mediated immunity to varicella-zoster virus glycoprotein E co-lyophilized with a cationic liposome-based adjuvant in mice. Vaccine 37, 21312141 (2019).
Article CAS Google Scholar
Wui, S. R. et al. The effect of a TLR4 agonist/cationic liposome adjuvant on varicella-zoster virus glycoprotein E vaccine efficacy: antigen presentation, uptake, and delivery to lymph nodes. Pharmaceutics 13, 390 (2021).
Article CAS PubMed Central Google Scholar
Moliva, J. I. et al. Selective delipidation of Mycobacterium bovis BCG enables direct pulmonary vaccination and enhances protection against Mycobacterium tuberculosis. Mucosal Immunol. 12, 805815 (2019).
Article CAS PubMed Central Google Scholar
Woodworth, J. S. et al. Mucosal boosting of H56:CAF01 immunization promotes lung-localized T cells and an accelerated pulmonary response to Mycobacterium tuberculosis infection without enhancing vaccine protection. Mucosal Immunol. 12, 816826 (2019).
Article CAS Google Scholar
Van Dis, E. et al. STING-activating adjuvants elicit a Th17 immune response and protect against Mycobacterium tuberculosis infection. Cell Rep. 23, 14351447 (2018).
Article PubMed Central Google Scholar
Jeon, B. Y. et al. Mycobacterium bovis BCG immunization induces protective immunity against nine different Mycobacterium tuberculosis strains in mice. Infect. Immun. 76, 51735180 (2008).
Article CAS PubMed Central Google Scholar
Abebe, F. & Bjune, G. The emergence of Beijing family genotypes of Mycobacterium tuberculosis and low-level protection by bacille Calmette-Guerin (BCG) vaccines: is there a link? Clin. Exp. Immunol. 145, 389397 (2006).
Article CAS PubMed Central Google Scholar
Gagneux, S. et al. Variable host-pathogen compatibility in Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA 103, 28692873 (2006).
Article ADS CAS PubMed Central Google Scholar
Koleske, B. N., Jacobs, W. R. Jr. & Bishai, W. R. The Mycobacterium tuberculosis genome at 25 years: lessons and lingering questions. J. Clin. Investig. 133, e173156 (2023).
Article PubMed Central Google Scholar
McShane, H. & Williams, A. A review of preclinical animal models utilised for TB vaccine evaluation in the context of recent human efficacy data. Tuberculosis 94, 105110 (2014).
Article Google Scholar
Henao-Tamayo, M. et al. The efficacy of the BCG vaccine against newly emerging clinical strains of Mycobacterium tuberculosis. PLoS ONE 10, e0136500 (2015).
Article PubMed Central Google Scholar
Kwon, K. W. et al. BCGDeltaBCG1419c increased memory CD8(+) T cell-associated immunogenicity and mitigated pulmonary inflammation compared with BCG in a model of chronic tuberculosis. Sci. Rep. 12, 15824 (2022).
Article ADS CAS PubMed Central Google Scholar
Groschel, M. I. et al. Recombinant BCG expressing ESX-1 of Mycobacterium marinum combines low virulence with cytosolic immune signaling and improved TB protection. Cell Rep. 18, 27522765 (2017).
Article CAS Google Scholar
Choi, H. G. et al. Antigen-specific IFN-gamma/IL-17-Co-producing CD4(+) T-cells are the determinants for protective efficacy of tuberculosis subunit vaccine. Vaccines 8, 300 (2020).
Article CAS PubMed Central Google Scholar
Kwon, K. W. et al. Immunogenicity and protective efficacy of RipA, a peptidoglycan hydrolase, against Mycobacterium tuberculosis Beijing outbreak strains. Vaccine (2024). Online ahead of print.
Niu, H. et al. Multi-stage tuberculosis subunit vaccine candidate LT69 provides high protection against Mycobacterium tuberculosis infection in mice. PLoS ONE 10, e0130641 (2015).
Article PubMed Central Google Scholar
Weinrich Olsen, A., van Pinxteren, L. A., Meng Okkels, L., Birk Rasmussen, P. & Andersen, P. Protection of mice with a tuberculosis subunit vaccine based on a fusion protein of antigen 85b and esat-6. Infect. Immun. 69, 27732778 (2001).
Article CAS Google Scholar
Nandakumar, S. et al. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis. Sci. Rep. 6, 25837 (2016).
Article ADS CAS PubMed Central Google Scholar
Sakai, S. et al. Cutting edge: control of Mycobacterium tuberculosis infection by a subset of lung parenchyma-homing CD4 T cells. J. Immunol. 192, 29652969 (2014).
Article CAS Google Scholar
Lindenstrom, T. et al. T cells primed by live mycobacteria versus a tuberculosis subunit vaccine exhibit distinct functional properties. EBioMedicine 27, 2739 (2018).
Article Google Scholar
Shanmugasundaram, U. et al. Pulmonary Mycobacterium tuberculosis control associates with CXCR3- and CCR6-expressing antigen-specific Th1 and Th17 cell recruitment. JCI Insight 5, e137858 (2020).
Article PubMed Central Google Scholar
Lin, T. W. et al. Tag-free SARS-CoV-2 receptor binding domain (RBD), but not C-terminal tagged SARS-CoV-2 RBD, induces a rapid and potent neutralizing antibody response. Vaccines 10, 1839 (2022).
Article CAS PubMed Central Google Scholar
Zhang, Y. Advances in the treatment of tuberculosis. Clin. Pharmacol. Ther. 82, 595600 (2007).
Article CAS Google Scholar
Lin, P. L. et al. The multistage vaccine H56 boosts the effects of BCG to protect cynomolgus macaques against active tuberculosis and reactivation of latent Mycobacterium tuberculosis infection. J. Clin. Investig. 122, 303314 (2012).
Article ADS CAS Google Scholar
Andersen, P. & Kaufmann, S. H. Novel vaccination strategies against tuberculosis. Cold Spring Harb. Perspect. Med. 4, a018523 (2014).
Article PubMed Central Google Scholar
Liu, X. et al. A multistage mycobacterium tuberculosis subunit vaccine LT70 including latency antigen Rv2626c induces long-term protection against tuberculosis. Hum. Vaccines Immunother. 12, 16701677 (2016).
Google Scholar
Coppola, M. et al. Synthetic long peptide derived from Mycobacterium tuberculosis latency antigen Rv1733c protects against tuberculosis. Clin. Vaccin. Immunol. 22, 10601069 (2015).
Article CAS Google Scholar
Choi, H. G. et al. Rv2299c, a novel dendritic cell-activating antigen of Mycobacterium tuberculosis, fused-ESAT-6 subunit vaccine confers improved and durable protection against the hypervirulent strain HN878 in mice. Oncotarget 8, 1994719967 (2017).
Article PubMed Central Google Scholar
Kim, J. S. et al. Mycobacterium tuberculosis RpfB drives Th1-type T cell immunity via a TLR4-dependent activation of dendritic cells. J. Leukoc. Biol. 94, 733749 (2013).
Article CAS Google Scholar
Choi, H. G. et al. Mycobacterium tuberculosis RpfE promotes simultaneous Th1- and Th17-type T-cell immunity via TLR4-dependent maturation of dendritic cells. Eur. J. Immunol. 45, 19571971 (2015).
Article CAS Google Scholar
Choi, H. H. et al. PPE39 of the Mycobacterium tuberculosis strain Beijing/K induces Th1-cell polarization through dendritic cell maturation. J. Cell Sci. 132, jcs228700 (2019).
Kwon, K. W. et al. Vaccine efficacy of a Mycobacterium tuberculosis Beijing-specific proline-glutamic acid (PE) antigen against highly virulent outbreak isolates. FASEB J. 33, 64836496 (2019).
Article CAS Google Scholar
Saylor, K., Gillam, F., Lohneis, T. & Zhang, C. Designs of antigen structure and composition for improved protein-based vaccine efficacy. Front. Immunol. 11, 283 (2020).
Article CAS PubMed Central Google Scholar
EMAs safety committee (PRAC)concluded that there was insufficient evidence to establish a causal association between the COVID-19 vaccines Comirnaty and Spikevax and cases of postmenopausal bleeding.
Postmenopausal bleeding is commonly defined as vaginal bleeding occurring one year or more after the last menstrual period. Postmenopausal bleeding is always considered abnormal and can be a symptom of serious medical conditions.
Recently, new information emerged from the medical literature as well as post-authorisation data that prompted investigation into postmenopausal bleeding with the two vaccines.
The PRAC assessed all available data, including findings from literature, and available post-marketing spontaneous reports of suspected adverse reactions.
After careful review, thePRACconsidered that the available data do not support a causal association and an update of theproduct informationfor either vaccine is not warranted.
The committee will continue to monitor this issue for both Comirnaty and Spikevax through the established safety monitoring practices.
New Centers for Disease Control and Prevention datais showing that newly released RSV vaccines are highly effective at keeping infants from becoming hospitalized.
The CDC says nirsevimab was 90% effective at preventing RSV-associated hospitalization in infants during their first RSV season. Nirsevimab wasapproved for babies and toddlers in July 2023.
The real-world usage of nirsevimab so far has outperformed data from clinical trials. Prior to its release, officials said nirsevimab reduced the risk of hospitalizations related to RSV among infants by 70%-75%.
"The current RSV season is the first time nirsevimab was available to protect infants from severe RSV, so the data released today are the first United States estimates of nirsevimab effectiveness in protecting infants against RSV-related hospitalization in their first season of potential exposure to the virus," the CDC said.
The study looked at 699 infants from October 2023 through February 2024. CDC officials did caution that its overall effectiveness may be lower once a full RSV season is complete. Generally, RSV activity declines in late March.
According to the CDC, RSV causes 58,000 hospitalizations annually among children under age 5.
SEE MORE: CDC: 128 pregnant people and 25 infants received the wrong RSV shot
The CDC said those most at risk for RSV include premature infants; very young infants, especially those 6 months and younger; and children younger than 2 years old with chronic lung disease or congenital heart disease.
Adults and older children who are healthy tend to have mild cases if infected. Early symptoms tend to include a runny nose, a decrease in appetite, and cough. Those symptoms can worsen, causing inflammation of the small airways in the lung.
The vaccine is recommended for all infants younger than 8 months born during or entering their first RSV season, if their mother did not get a maternal RSV vaccine. Another option is for pregnant people to get vaccinated during weeks 32 through 36 of their pregnancy if that period falls between September and January.
Trending stories at Scrippsnews.com
6 March 2024
The vaccine hub will be built on AstraZeneca's existing site in Speke
A 450m vaccine manufacturing hub is set to be built in the north west of England, the chancellor has announced.
Jeremy Hunt said in his Budget speech that AstraZeneca planned to invest the 450m in Speke in Liverpool as part of a total investment of 650m in the UK.
The Treasury said the investment was dependent on "mutual agreement with the UK government and third parties".
AstraZeneca said it demonstrated their "ongoing confidence in UK life sciences".
As part of the 650m total investment the pharmaceutical company said it would also expand its footprint on the Cambridge Biomedical Campus.
Mr Hunt said: "AstraZeneca's investment plans are a vote of confidence in the attractiveness of UK as a life sciences superpower and strengthen our resilience for future health emergencies."
The investment in Liverpool was said by the government to be for the research, development, and manufacture of vaccines, "building on the site's current role in supplying the world leading childhood vaccination programme".
The new facility would be designed and built to be operationally net zero with power supplied from renewable energy sources.
AstraZeneca's chief executive officer, Sir Pascal Soriot, said the planned investment would "enhance the UK's pandemic preparedness and demonstrates our ongoing confidence in UK life sciences".
He added: "We will continue to support the UK in driving innovation and patient access, building on the strong foundations which have been put in place."
Dr Isabel Oliver, chief scientific officer at the UK Health Security Agency, said: "This investment will bolster the development of the UK's vaccine capabilities and life sciences sector - critical components of the country's resilience to future health threats."
In a statement to announce the plans, the Treasury said the investment needed the agreement of the UK Government and "third parties" and depended on "successful completion of regulatory processes".
New Centers for Disease Control and Prevention datais showing that newly released RSV vaccines are highly effective at keeping infants from becoming hospitalized.
The CDC says nirsevimab was 90% effective at preventing RSV-associated hospitalization in infants during their first RSV season. Nirsevimab wasapproved for babies and toddlers in July 2023.
The real-world usage of nirsevimab so far has outperformed data from clinical trials. Prior to its release, officials said nirsevimab reduced the risk of hospitalizations related to RSV among infants by 70%-75%.
"The current RSV season is the first time nirsevimab was available to protect infants from severe RSV, so the data released today are the first United States estimates of nirsevimab effectiveness in protecting infants against RSV-related hospitalization in their first season of potential exposure to the virus," the CDC said.
The study looked at 699 infants from October 2023 through February 2024. CDC officials did caution that its overall effectiveness may be lower once a full RSV season is complete. Generally, RSV activity declines in late March.
According to the CDC, RSV causes 58,000 hospitalizations annually among children under age 5.
SEE MORE: CDC: 128 pregnant people and 25 infants received the wrong RSV shot
The CDC said those most at risk for RSV include premature infants; very young infants, especially those 6 months and younger; and children younger than 2 years old with chronic lung disease or congenital heart disease.
Adults and older children who are healthy tend to have mild cases if infected. Early symptoms tend to include a runny nose, a decrease in appetite, and cough. Those symptoms can worsen, causing inflammation of the small airways in the lung.
The vaccine is recommended for all infants younger than 8 months born during or entering their first RSV season, if their mother did not get a maternal RSV vaccine. Another option is for pregnant people to get vaccinated during weeks 32 through 36 of their pregnancy if that period falls between September and January.
Trending stories at Scrippsnews.com
This week, Western Australia announced a state government-funded immunisation program against respiratory syncytial virus (RSV). Its the first Australian state or territory to do so.
All babies under eight months old and those aged eight to 19 months at increased risk of severe RSV infection will be eligible for the immunisation in WA this year.
RSV can cause serious illness in children, and news headlines have welcomed WAs impending rollout of vaccinations against the virus.
But this immunisation differs from other routine childhood vaccines.
RSV is the most common cause of respiratory infection in young children. By the age of two, almost all children show evidence theyve been exposed to the virus.
Estimates suggest 2-3% of infants are hospitalised with RSV with infection involving the airways and lungs. Infants under three months are at highest risk. RSV can also have long-lasting effects on children theres a well-established link between RSV and subsequent wheezing illnesses and asthma.
RSV can also be a problem for the elderly and people with underlying health conditions such as those with weakened immune systems.
Read more: An RSV vaccine has been approved for people over 60. But what about young children?
Antibodies are a key part of the immune system that protect people against many viral infections, including RSV. Theyre usually generated in response to infection or a vaccine, and work by attaching to proteins on the surface of RSV, therefore preventing the virus from invading the cells that line the airways and lungs.
The problem in newborn babies (who are at the highest risk of severe RSV infection) is that previous vaccines have not generated sufficient antibodies to provide protection.
So, two strategies have been developed to protect young children against RSV. These strategies are both referred to as passive immunisation, because children receive protective antibodies from outside the body. This is different to active immunisation where we give a child a vaccine so they can generate their own antibodies.
One way to deliver passive immunity to young infants is by vaccinating their mothers during pregnancy. Maternal immunisation has been shown to be effective at protecting infants from other infections, including influenza, whooping cough (pertussis), tetanus and COVID.
By delivering a single RSV vaccine to pregnant women, antibodies are generated by the mother and transported across the placenta, providing passive immunity and protection to the baby for around the first six months of life. In a clinical trial, giving an RSV vaccine in late pregnancy reduced RSV in young infants by approximately 70%. But RSV vaccines for pregnant women are not yet available in Australia.
Read more: RSV is everywhere right now. What parents need to know about respiratory syncytial virus
The other passive immunisation strategy relies on manufactured long-acting antibodies (known as monoclonal antibodies), which can be delivered by injection to young children.
This is what will be offered in WA. Nirsevimab (also known as Beyfortus) is a long-acting antibody that Australias Therapeutic Goods Administration (TGA) approved in November 2023.
Nirsevimab binds specifically to RSV and remains in the body for several months after injection. In a key clinical trial nirsevimab was shown to reduce RSV infections by about 75% for up to five months.
Several European countries have recently implemented infant programs with nirsevimab and are reporting significantly lower RSV hospitalisation rates in babies.
Antibody therapies in various forms have been used for more than a century for the prevention and treatment of a range of conditions, dating from serotherapy for tetanus, diphtheria and snake bite in the late 1800s.
Licensed antibody products are rigorously tested in clinical trials and through post-marketing surveillance to ensure their safety.
For nirsevimab specifically, the clinical trial mentioned above included over 1,400 infants. Adverse events were reported at similar rates in the nirsevimab and placebo groups, and no serious adverse events relating to treatment were reported. No significant safety concerns have been identified in the real-world rollout in the northern hemisphere either.
RSV usually takes hold just before the flu season in southern states, and circulates year-round in tropical areas. While influenza almost disappeared during the COVID pandemic, there were ongoing cases of RSV, albeit with a disruption to the normal seasonal pattern.
Since 2022, RSV has resumed its normal seasonal pattern. The WA government says the immunisations will be available from April, which is timely in anticipation of the 2024 season.
Read more: RSV is a common winter illness in children. Why did it see a summer surge in Australia this year?
Free access to an immunisation against RSV should significantly benefit young children and families in WA, keeping children out of hospital this winter.
Whether other states will follow WAs lead is uncertain at this stage, and we dont yet know whether nirsevimab will in time become part of the National Immunisation Program, meaning it would be available for free nation-wide.
Ensuring equitable access, particularly for those at greatest risk of severe RSV infection, must be prioritised to ensure maximum benefit for all children and families.
Nirsevimab is likely to be the first of many tools to prevent RSV in children. A maternal RSV vaccine is currently under assessment by the TGA and Pharmaceutical Benefits Advisory Committee (PBAC). A vaccine for older Australians, Arexvy, is registered and is also being assessed by the PBAC, with additional vaccines expected to be available in the future.
These developments highlight the future of RSV prevention and also the significant potential for monoclonal antibodies to play a greater role in preventing infections as part of public health programs.
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(NEXSTAR) More than two years after being removed from the ABC soap opera General Hospital following a dispute over the COVID-19 vaccine, actor Steve Burton has returned to the show.
Burton appeared on Mondays episode of General Hospital, roughly one month after the actor teased his return in an Instagram video apparently filmed on the shows set.
Hey hey, back at home, Burton told fans at the time.
Burton, who joined the show in 1992 as Jason Morgan, had first revealed to fans in November 2021 that the producers let [him] go because of the vaccine mandate. He explained at the time that he had applied for medical and religious exemptions, but was denied.
ABC confirmed the decision to The Hollywood Reporter in 2021, explaining that the networks policy required cast and crew working in areas where actors werent masked to be vaccinated.
The verified Instagram page for General Hospital shared a video of Burton, 53, on Tuesday.
It just feels really good to be back on set with my people, Burton says during the clip, which also shows him walking on set and explaining how hes approaching his character upon his return.
After leaving General Hospital, Burton reprised his Days of Our Lives role as Navy SEAL Harris Michaels on the shows spin-off miniseries Beyond Salem in 2022, and also on Days last year, USA Today reports. Burton announced last month that he would be leaving the series, but a spokesperson told USA Today that his character will remain on the show for the coming months.
Shortly before Burton left General Hospital, the show parted ways with Ingo Rademacher, who had played Jasper Jax Jacks on the soap opera since 1996, for refusing to complywith the shows vaccine mandate. Rademacher later sued ABC over the mandate, but a Los Angeles judge sided with ABC in the case in June 2023.
In November 2022, most Disney shows dropped their vaccine mandates, Deadline reported. (The Walt Disney Company owns ABC.)
CLAIM
Whooping cough vaccine was never necessary, DTaP vaccine is linked to sudden infant death syndrome
DETAILS
Misleading: Looking at deaths alone doesnt provide us the full picture of a vaccines impact. The impact of whooping cough vaccination can be seen in whooping cough incidence, which fell dramatically after the vaccine was introduced in the 1940s. While whooping cough deaths had fallen before that, this doesnt make the vaccine unnecessary. The disease produces potentially serious complications even if the patient survives. Factually inaccurate: Studies have found no association between the DTaP vaccine and sudden infant death syndrome (SIDS). Childhood vaccination isnt a risk factor for SIDS.
KEY TAKE AWAY
Whooping cough causes the body to produce very thick mucus that can block the airways, which induces violent coughing. This coughing, also called paroxysmal coughing, can be strong enough to break ribs, burst blood vessels, and produce hernias. Other complications associated with whooping cough are bacterial pneumonia, seizures, and brain inflammation. Childhood vaccination helps to prevent diseases that are associated with potentially serious complications leading to disability and death.
The reels caption concluded by advocating for people to let their immune systems do its job, naturally, in effect, implying people would be better off taking their chances with disease than if they got vaccinated.
The reel, which was posted by the Instagram account @you.dont.know.jac, was viewed more than 17,900 times. The account has more than 83,000 followers and is run by an individual named Jaclyn Simone, who also claims vaccines cause encephalitis and autism (they dont) and promotes an oil that allegedly detoxes and treats autism (theres no evidence this works).
The DTaP vaccine targets three diseases: diphtheria, tetanus, and pertussis (whooping cough). All three diseases are caused by toxin-producing bacteria. Unlike other vaccines which target the harmful microorganism, the DTaP vaccine targets the toxins that the microorganisms produce, as it is the toxins that produce the disease.
As we will explain below, the claims made in the reel misrepresent published articles in journals and potentially place people at risk of serious complications from vaccine-preventable diseases.
To support her suggestion that the whooping cough vaccine is unnecessary, Simone pointed to a graph of pertussis mortality in the U.S. It showed that deaths from whooping cough had declined before the 1940s, when the whooping cough vaccine became available.
Using reverse image search, we were able to identify a similar-looking graph published on this website, bearing the URL healthsentinel.com in a corner. The website healthsentinel.com is a now-defunct, anonymous website that pushed claims similar to those made in the reel, as can be seen in this archive.
The graph indicated that the data was sourced from the reports Vital Statistics Rate in the United States 1940-1960 and the Historical Statistics of the United States, Colonial Times to 1957, published in 1968 and 1975, respectively.
Now, the issue with the claim isnt that the data comes from unreliable sources or that its necessarily inaccurate, but that it provides a limited perspective of the vaccines impact on public health.
As David Gorski, a surgical oncologist and editor of Science-Based Medicine, explained in this 2010 article, deaths from various vaccine-preventable diseases did decline as a result of improvements in supportive care. For instance, the development of the iron lung meant that fewer children died from polio-associated paralysis of the breathing muscles.
However, looking only at deaths doesnt give us the whole picture. We get a more complete understanding of the impact that vaccines had on infectious diseases when we look at the incidence rate as well as the mortality rate.
As we can see from the graph below, cases of whooping cough fell after the first combination diphtheria-tetanus-pertussis (DTP) vaccine was made available (Figure 1). In the 1940s, when the vaccine was first made available, the number of whooping cough cases frequently exceeded 100,000 cases per year. By 1965, reports fell to fewer than 10,000.
Figure 1 Pertussis cases reported to the National Notifiable Diseases Surveillance System (NNDSS) in the United States. The DTP vaccine was the first combination vaccine against diphtheria, tetanus, and pertussis. This vaccine contained killed Bordetella pertussis, the causative agent of pertussis, in addition to the inactivated pertussis toxin. Its successor, the DTaP vaccine, contains only the pertussis toxin. The Tdap vaccine is given to those older than seven years old and is generally used as a booster for teenagers and adults. Source: NNDSS. Retrieved on 5 March 2024.
Moreover, focusing only on deaths means neglecting the diseases harmful impact on those who survive, as we will show below.
As explained earlier, the three diseases that the DTaP vaccine targets are diseases caused by toxins from bacteria, namely Corynebacterium diphtheriae, Clostridium tetani, and Bordetella pertussis. This is why, unlike many other vaccines, the DTaP vaccine targets the toxins released by the bacteria rather than the bacteria themselves.
The Instagram reel advocated for people to allow nature to take its course, implicitly encouraging infection in lieu of vaccination. However, all three diseases can produce great distress and potentially serious complications, even if they dont ultimately kill.
Whooping cough causes the body to produce very thick mucus that can block the airways, which induces violent coughing. This coughing, also called paroxysmal coughing, can be strong enough to break ribs, burst blood vessels, and produce hernias. Other complications associated with whooping cough are bacterial pneumonia, seizures, and brain inflammation.
Diphtheria can occur in two forms, respiratory and non-respiratory. The respiratory form, which is more common, manifests in fever, sore throat, and notably membranes forming in the airways that may lead to respiratory obstruction. The toxin produced by the bacterium can also cause myocarditis and neuritis.
Tetanus, also known as lockjaw, leads to difficulty in swallowing, muscle spasms (involuntary muscle contraction), and seizures. The spasms can be strong enough to break bones.
Unlike many infectious diseases, getting tetanus doesnt confer immunity to the disease. This is because tetanus toxin is highly potent and so only a small amount is needed to produce disease. This means that during infection, the body isnt exposed to a level of toxin high enough to generate a protective immune response. At the moment, the only way of acquiring immunity to tetanus is through vaccination.
Many people do survive these diseases, and in many cases, infection can produce protective immunity. Yet the risk associated with simply letting our immune systems handle them, as the reel advocates, is that infection carries significant risks of disability and death. For instance, an unvaccinated boy in Oregon contracted tetanus through a cut. He spent 57 days in hospitalmore than 40 of those days in intensive careand had to undergo rehabilitation to walk again.
The reel cited a report from 1946, published in the Journal of the American Medical Association, documenting the deaths of twin boys shortly after receiving the diphtheria and pertussis vaccine[1]. The reel then went on to talk about sudden infant death syndrome (SIDS), claiming that SIDS spikes after well visits, a reference to well-child visits.
Well-child visits are scheduled screenings and assessments for healthy children. They are also when childhood vaccines are normally given. The juxtaposition of the case report and the problem of SIDS, implicitly suggested that the DTaP vaccine causes SIDS.
SIDS is the sudden death of a baby before one year of age that doesnt have a known cause, despite a full investigation. However, scientific studies have found no association between SIDS and the DTaP vaccine[2-4]. There are various risk factors for SIDS, such as an underlying but undetected medical condition and placing a baby to sleep on their stomach. But childhood vaccination isnt one of them.
The Vaccine Education Center at the Childrens Hospital of Philadelphia explains:
[S]ince immunizations are given to about 90 percent of children less than 1 year of age, and about 1,600 cases of SIDS occur every year, it would be expected, statistically, that every year about 50 cases of SIDS will occur within 24 hours of receipt of a vaccine. However, because the incidence of SIDS is the same in children who do or do not receive vaccines, we know that SIDS is not caused by vaccines.
Moreover, the 1946 report that the reel cited stated that the twins had died from anaphylaxis, a severe allergic reaction, hours after the second DTaP dose. A review by the U.S. Institute of Medicine, also citing the same report, discussed the deaths in the context of anaphylaxis[5]. This isnt compatible with the reels implication that the deaths were due to SIDS.
The reel also cited a 1948 article in the journal Pediatrics, which it claimed discusses brain damage from the vaccine and concluded that the vaccine risk was just far too great to continue.
But these statements grossly misrepresent the article.
The article reported that Childrens Hospital records showed 15 cases of acute cerebral symptoms occurring in children after pertussis vaccination in the past ten years. But it didnt establish that these cases were caused by the vaccine, contrary to Simones assertion. The sole fact that an adverse event occurred after vaccination isnt sufficient evidence that the vaccine caused the event.
And the authors came to the opposite conclusion, as shown in their abstract[6]:
In view of the impressive evidence of the effectiveness of prophylactic pertussis vaccine now accumulating, it seems likely that babies are safer vaccinated than not.
The DTaP vaccine helps to prevent diseases caused by toxin-producing bacteria, which can have devastating consequences for children, even if they survive. While infection can confer immunity against a future infection in many cases, it doesnt always do soas in the case of tetanusand carries the risk of disability and death.
Ultimately, as the saying goes, prevention is worth a pound of cure. Getting vaccinated enables us to acquire protective immunity to potentially dangerous diseases without having to run the risks associated with infection.
