-
The Lancet. Microbe Jan 2024
Topics: Humans; Diphtheria; Nigeria; Corynebacterium diphtheriae; Corynebacterium; Disease Outbreaks
PubMed: 37951229
DOI: 10.1016/S2666-5247(23)00330-0 -
Blood Advances Feb 2024CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a...
CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/-VEN in combination. The recommended phase 2 dose of TAG was 12 μg/kg/day for 3 days, with 7-day AZA +/- 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643.
Topics: Adult; Aged; Humans; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Interleukin-3 Receptor alpha Subunit; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-bcl-2; Recombinant Fusion Proteins; Sulfonamides
PubMed: 38052038
DOI: 10.1182/bloodadvances.2023011721 -
Infectious Diseases and Therapy Aug 2023Vaccination in pregnancy using a tetanus toxoid, reduced dose diphtheria toxoid, and reduced dose acellular pertussis (Tdap) vaccine is important for prevention of... (Review)
Review
Vaccination in pregnancy using a tetanus toxoid, reduced dose diphtheria toxoid, and reduced dose acellular pertussis (Tdap) vaccine is important for prevention of severe pertussis disease in young infants. The objectives of this systematic literature review were to search for original research studies evaluating the vaccine effectiveness, immunogenicity, and safety of Adacel/Adacel-Polio used during pregnancy to prevent pertussis disease in young infants. Medical databases used included EMBASE, BIOSIS Previews, and Chemical Abstracts, with search terms related to pregnancy, vaccines/immunization, safety, pertussis, effectiveness/efficacy, and immune response; other potentially eligible reports were included where applicable. Search results were restricted to literature published from 1 January 1995 to 26 July 2021. A total of 2021 articles and 4 other reports were identified for primary review. A total of 49 publications qualified for inclusion after primary and secondary reviews. Effectiveness studies of Adacel or Adacel-Polio given in pregnancy consistently showed high levels of protection from pertussis disease in the newborn (vaccine effectiveness: 91-93%). In immunogenicity studies, the response in pregnant women was consistent with that of non-pregnant women. Infants of mothers vaccinated with Adacel or Adacel-Polio in pregnancy had higher anti-pertussis antibody levels at birth and at 2 months of age compared to infants born to women vaccinated with comparator vaccines, placebo, or those not vaccinated during pregnancy. There was evidence of a slightly decreased response to primary pertussis vaccination in infants of mothers vaccinated with Adacel or Adacel-Polio, but this was not thought to be clinically significant. In safety studies, Adacel or Adacel-Polio vaccination was well tolerated by pregnant woman and not associated with pregnancy, postpartum, or neonatal complications. In conclusion, Adacel or Adacel-Polio vaccination in pregnancy is highly effective in protecting young infants from pertussis disease, with a favorable safety profile for both pregnant women and their infants.
PubMed: 37653123
DOI: 10.1007/s40121-023-00847-5 -
Vaccine Oct 2023In 2019, the 3 + 1 schedule for children's vaccination (2-4-6-18 months old) was changed for a reduced 2 + 1 schedule (2-4-12 months old) in Quebec, Canada. We... (Observational Study)
Observational Study
BACKGROUND
In 2019, the 3 + 1 schedule for children's vaccination (2-4-6-18 months old) was changed for a reduced 2 + 1 schedule (2-4-12 months old) in Quebec, Canada. We compared the post-booster anti-pertussis and anti-pneumococcus IgG antibody concentrations among children of Tdap-vaccinated and unvaccinated mothers for different vaccine schedules and vaccine formulations.
METHODS
We conducted an observational cohort study. An invitation letter to potential participants was provided during a routine vaccination visit. Children's blood samples were analyzed post-booster at 13 (2 + 1 schedule) or 19 (3 + 1 schedule) months of age for antibodies against pertussis antigens (pertussis toxin (PT), filamentous hemagglutinin (FHA) and pertactin (PRN)) and pneumococcal antigens (serotypes 4, 18C, 19A, and 19F). IgG concentrations among children of Tdap-vaccinated and unvaccinated mothers for each vaccination schedule were compared using geometric mean concentrations (GMCs) and GMC ratios (GMRs), adjusting for potentially immune-response-influencing factors (aGMR). Serotype-specific pneumococcal seroprotection rates were also compared.
RESULTS
A total of 360 children were included for pertussis analysis and 248 for pneumococcal analysis. For the 2 + 1 schedule, 13-month-old children of Tdap-vaccinated mothers had lower GMCs against PT, FHA, and PRN, with aGMR (95 %CI) of 0.77 (0.65-0.90), 0.66 (0.55-0.79), 0.72 (0.52-0.99), respectively. For the 3 + 1 schedule, at 19 months old, the interference appeared to be attenuated (higher aGMR values). GMCs against PT were slightly higher in the 3 + 1 than the 2 + 1 schedule: 126.5 IU/ml vs 91.6 IU/ml; aGMR = 1.27. GMCs against PT, FHA and PRN were slightly higher among children who received Infanrix hexa® compared to those who received Pediacel® at 12 months old. For pneumococcal antibodies, at 13 months old, there was no strong evidence of immune interference in children of Tdap-vaccinated mothers.
CONCLUSION
Infant vaccination schedule may influence immune interference associated with maternal Tdap vaccination. More studies are needed to assess the clinical impact of this interference on children's protection.
Topics: Female; Humans; Infant; Pregnancy; Antibodies, Bacterial; Bacterial Vaccines; Cohort Studies; Diphtheria-Tetanus-acellular Pertussis Vaccines; Immunization Schedule; Pertussis Toxin; Pertussis Vaccine; Pneumococcal Vaccines; Whooping Cough
PubMed: 37816653
DOI: 10.1016/j.vaccine.2023.09.063 -
International Journal For Equity in... Aug 2023Inequity in maternal-child health services is a challenge to global health as it hinders the achievement of Sustainable Development Goals (SDGs) and Universal Health...
INTRODUCTION
Inequity in maternal-child health services is a challenge to global health as it hinders the achievement of Sustainable Development Goals (SDGs) and Universal Health Coverage. Though the Association of Southeast Asian Nations (ASEAN) has made remarkable achievements in maternal-child health, there remain gaps in reaching global goals. This study aimed to compare and investigate the inequity in maternal-child health (MCH) services in ASEAN member states to help guide policy decisions to improve equitable health services in the SDG era and beyond.
METHODS
Using the WHO Health Inequality Monitor, we identified inequity summary measures for five MCH services in ASEAN member states from 1993 to 2021: antenatal care, births attended by skilled health personnel, diphtheria, tetanus and pertussis (DTP3) immunization, measles immunization, and polio immunization. We divided the analysis dimension of inequity into urban-rural inequity, economic status inequity, and sub-regional inequity. Trends of absolute and relative inequity in every dimension of MCH services in ASEAN member states were examined with the principal component analysis (PCA).
RESULTS
The mean coverages of MCH services are 98.80% (Thailand), 86.72% (Cambodia), 84.54% (Viet Nam), 78.52 (Indonesia), 76.94% (Timor-Leste), 72.40% (Lao PDR), 68.10% (Philippines) and 48.52% (Myanmar) in 2021. Thailand have the lowest MCH services absolute inequity indexes of -1.945, followed by Vietnam (-1.449). Lao PDR and Myanmar have relatively higher MCH services absolute inequity indexes of 0.852 and 0.054 respectively. The service in Cambodia, Indonesia, and the Philippines is pro-specific regions (with subnational region absolute inequity indexes of -0.02, 0.01, and 1.01 respectively). The service in Myanmar is pro-rich (with economic status absolute inequity index of 0.43). The service in Lao PDR and Timor-Leste is pro-urban areas, pro-rich, and pro-specific regions.
CONCLUSION
The inequity of MCH services in ASEAN persists but is in a declining trend. Thailand and Vietnam have performed well in ensuring MCH services equity, while Laos and Myanmar are still facing serious inequity dilemmas. The progress of MCH service equity in Myanmar, Cambodia, the Philippines, and Indonesia is uneven. It is acceptable to learn from the successful experiences of Thailand and Vietnam to improve the equities in other ASEAN countries. Policies should be developed according to the specific types of MCH inequity in member states to improve equity levels.
Topics: Humans; Female; Pregnancy; Maternal-Child Health Services; Health Status Disparities; Philippines; Prenatal Care; Thailand
PubMed: 37550702
DOI: 10.1186/s12939-023-01974-8 -
Communicable Diseases Intelligence... Oct 2023Background We examined trends in tetanus notification, hospitalisation and death data from 2003-2019 to assess the impact of adult tetanus booster recommendations in...
Background We examined trends in tetanus notification, hospitalisation and death data from 2003-2019 to assess the impact of adult tetanus booster recommendations in Australia. Methods Tetanus notifications and deaths from the National Notifiable Diseases Surveillance System; hospitalisations from the Australian Institute of Health and Welfare National Hospital Morbidity Database; and deaths from the Australian Coordinating Registry were analysed by age group, sex, Aboriginal and Torres Strait Islander status and state/territory. Annual rates were calculated using Australian Bureau of Statistics mid-year estimated resident populations from 2003-2019 as denominators. To assess the impact of a recommended booster dose of reduced antigen content diphtheria-tetanus-acellular pertussis (dTpa) vaccine for adults aged ≥ 65 years, notification, hospitalisation and death rates of tetanus per 100,000 population were compared pre (2003-2012) and post (2013-2019) the recommendation's introduction. Results There were 63 notifications of tetanus from 2003-2019 with an average annual incidence rate of 0.02/100,000. Similar to previous studies, the burden of tetanus in the Australian population continues to disproportionately affect the elderly, with those aged ≥ 65 years encompassing 63% (40/63) of notifications and 100% (11/11) of the deaths observed in this timeframe. Following the introduction of a recommendation for those aged ≥ 65 years to receive a dTpa booster, average annual notification and hospitalisation rates in those aged ≥ 65 years were significantly lower (notifications: 0.11/100,000 in 2003-2012 and 0.05/100,000 in 2013-2019, p = 0.01; hospitalisations: 0.24/100,000 in 2003-2012 and 0.10/100,000 in 2013-2019, p = 0.01]). The average annual death rate was similar in the two periods (0.002/100,000), although based on small numbers. Conclusions The findings of this analysis suggest a positive impact from the 2013 recommendation. However, the burden is still disproportionately higher in those aged ≥ 65 years and strategies to improve vaccination coverage in older Australians are recommended.
Topics: Adult; Aged; Humans; Tetanus; Vaccination; Vaccine-Preventable Diseases; Australia; Diphtheria-Tetanus-acellular Pertussis Vaccines; Pentetic Acid
PubMed: 37857556
DOI: 10.33321/cdi.2023.47.61 -
International Journal of Molecular... Jul 2023Conventional targeted therapies for the treatment of cancer have limitations, including the development of acquired resistance. However, novel alternatives have emerged... (Review)
Review
Conventional targeted therapies for the treatment of cancer have limitations, including the development of acquired resistance. However, novel alternatives have emerged in the form of targeted therapies based on AB toxins. These biotoxins are a diverse group of highly poisonous molecules that show a nanomolar affinity for their target cell receptors, making them an invaluable source of ligands for biomedical applications. Bacterial AB toxins, in particular, are modular proteins that can be genetically engineered to develop high-affinity therapeutic compounds. These toxins consist of two distinct domains: a catalytically active domain and an innocuous domain that acts as a ligand, directing the catalytic domain to the target cells. Interestingly, many tumor cells show receptors on the surface that are recognized by AB toxins, making these high-affinity proteins promising tools for developing new methods for targeting anticancer therapies. Here we describe the structure and mechanisms of action of Diphtheria (Dtx), Anthrax (Atx), Shiga (Stx), and Cholera (Ctx) toxins, and review the potential uses of AB toxins in cancer therapy. We also discuss the main advances in this field, some successful results, and, finally, the possible development of innovative and precise applications in oncology based on engineered recombinant AB toxins.
Topics: Humans; Ligands; Bacterial Toxins; Neoplasms; Receptors, Cell Surface
PubMed: 37446406
DOI: 10.3390/ijms241311227 -
Vaccine: X Aug 2023Vaccination of pregnant women with tetanus, diphtheria, and acellular pertussis (Tdap) and influenza vaccines is desirable to reduce neonatal and maternal morbidity and...
INTRODUCTION
Vaccination of pregnant women with tetanus, diphtheria, and acellular pertussis (Tdap) and influenza vaccines is desirable to reduce neonatal and maternal morbidity and mortality. However, vaccine coverage rates and acceptance are frequently below recommended rates.
OBJECTIVES
To ascertain Tdap and influenza vaccine coverage rates in our population and to study the reasons behind sub-optimal rates.
METHOD
A survey was submitted to pregnant or in their puerperium women at the University Hospital of São Paulo University. Data were obtained during two consecutive influenza seasons (2017-2018), and vaccination was verified through vaccination chart checking. Respondents were classified according to their status as "Received Tdap" and "Didn't receive Tdap", and as "Know" or "Doesn't know" regarding their awareness of Tdap safety during pregnancy and protective effect on the newborn. Vaccine uptake and personal awareness of vaccination status were compared among these groups for Tdap and influenza vaccines.
RESULTS
In a studied sample of 207 patients (representative of the whole), coverage rates for Tdap and influenza vaccines were respectively 85.5% and 95.2%. Additionally, 84.5% received both vaccines. There was no vaccine refusal for Tdap and only 0.5% for influenza. For either Tdap or influenza vaccines, the main reason for not vaccinating was a lack of knowledge/information. Factors associated with not vaccinating Tdap during pregnancy were lower number of prenatal visits, being unemployed or freelance worker, not being aware of vaccine safety or its benefits for the baby, not being oriented by the doctor to be vaccinated, not being aware of personal vaccination status, and not having been vaccinated for influenza.
CONCLUSION
While influenza vaccination coverage during pregnancy was ideal, Tdap rates were below recommended values. Significant factors associated with better coverage for Tdap during pregnancy included being employed and not being self-employed, (not yet reported in the Americas) and being aware of personal vaccination status.
PubMed: 37519777
DOI: 10.1016/j.jvacx.2023.100351 -
Biological Psychiatry Jan 2024Deficient social interactions are a hallmark of major neuropsychiatric disorders, and accumulating evidence points to altered social reward and motivation as key...
BACKGROUND
Deficient social interactions are a hallmark of major neuropsychiatric disorders, and accumulating evidence points to altered social reward and motivation as key underlying mechanisms of these pathologies. In the present study, we further explored the role of the balance of activity between D and D receptor-expressing striatal projection neurons (D1R- and D2R-SPNs) in the control of social behavior, challenging the hypothesis that excessive D2R-SPN activity, rather than deficient D1R-SPN activity, compromises social behavior.
METHODS
We selectively ablated D1R- and D2R-SPNs using an inducible diphtheria toxin receptor-mediated cell targeting strategy and assessed social behavior as well as repetitive/perseverative behavior, motor function, and anxiety levels. We tested the effects of optogenetic stimulation of D2R-SPNs in the nucleus accumbens (NAc) and pharmacological compounds repressing D2R-SPN.
RESULTS
Targeted deletion of D1R-SPNs in the NAc blunted social behavior in mice, facilitated motor skill learning, and increased anxiety levels. These behaviors were normalized by pharmacological inhibition of D2R-SPN, which also repressed transcription in the efferent nucleus, the ventral pallidum. Ablation of D1R-SPNs in the dorsal striatum had no impact on social behavior but impaired motor skill learning and decreased anxiety levels. Deletion of D2R-SPNs in the NAc produced motor stereotypies but facilitated social behavior and impaired motor skill learning. We mimicked excessive D2R-SPN activity by optically stimulating D2R-SPNs in the NAc and observed a severe deficit in social interaction that was prevented by D2R-SPN pharmacological inhibition.
CONCLUSIONS
Repressing D2R-SPN activity may represent a promising therapeutic strategy to relieve social deficits in neuropsychiatric disorders.
Topics: Mice; Animals; Nucleus Accumbens; Neurons; Social Behavior; Motivation; Learning; Receptors, Dopamine D1
PubMed: 37207936
DOI: 10.1016/j.biopsych.2023.05.008 -
JCI Insight Jul 2023Resolution of T cell activation and inflammation is a key determinant of the lack of SIV disease progression in African green monkeys (AGMs). Although frequently...
Resolution of T cell activation and inflammation is a key determinant of the lack of SIV disease progression in African green monkeys (AGMs). Although frequently considered together, T cell activation occurs in response to viral stimulation of acquired immunity, while inflammation reflects innate immune responses to mucosal injury. We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs. This intervention abolished control of T cell immune activation beyond the transition from acute to chronic infection. Ontak had no effect on gut barrier integrity, microbial translocation, inflammation, and hypercoagulation, despite increasing T cell activation. Ontak administration increased macrophage counts yet decreased their activation. Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4+ T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs.
Topics: Animals; Chlorocebus aethiops; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Disease Progression; CD4-Positive T-Lymphocytes; Inflammation
PubMed: 37485874
DOI: 10.1172/jci.insight.161111