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EBioMedicine Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC,...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking.
METHODS
We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
FINDINGS
Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
INTERPRETATION
Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
FUNDING
German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
PubMed: 38941955
DOI: 10.1016/j.ebiom.2024.105219 -
PLOS Global Public Health 2024Nested serosurveys within routine service delivery platforms such as planned supplemental immunization activities (SIAs) provide an opportunity to collect information...
Feasibility and acceptability of collecting dried blood spots (DBS) from children after vaccination during supplementary immunization activities to estimate measles and rubella seroprevalence.
Nested serosurveys within routine service delivery platforms such as planned supplemental immunization activities (SIAs) provide an opportunity to collect information that can be used to answer valuable questions on the effectiveness and efficiency of the delivery model to inform future activities. However, integrating research data collection in SIAs is rarely done due to concerns it will negatively impact the program. We conducted a serosurvey nested within the November 2020 measles-rubella SIA integrated with the Child Health Week activities in Zambia to evaluate this approach. In-depth interviews with the study teams and vaccination campaign staff at the vaccination sites were conducted. Recorded interviews were transcribed, transcripts were coded and then grouped into themes based on a process evaluation framework. A multi-methods analytical approach was used to assess the feasibility and acceptability of collecting dried blood spots from children during the SIA. This included a quantitative assessment of participant enrollment. The serosurvey successfully enrolled 90% of children from Child Health Week due to close coordination and teamwork between the vaccination teams and serosurvey team, in addition to substantial social mobilization efforts. Continually adjusting the sampling interval that was used to select eligible children allowed us to enroll throughout the SIA and capture a representative sample of children in attendance although it was challenging for the staff involved. As vaccination programs aim to tailor their approaches to reach the hardest-to-reach children, embedding research questions in SIAs will allow evaluation of the successes and challenges and compare alternative approaches. Lessons learned from this experience collecting data during an SIA can be applicable to future research activities embedded in SIAs or other delivery platforms.
PubMed: 38941295
DOI: 10.1371/journal.pgph.0002985 -
Open Forum Infectious Diseases Jun 2024Antimicrobial resistance (AMR) is a global threat to infectious disease control, particularly among recently hospitalized children. We sought to determine the prevalence...
BACKGROUND
Antimicrobial resistance (AMR) is a global threat to infectious disease control, particularly among recently hospitalized children. We sought to determine the prevalence and mitigating factors of resistance in enteric among children discharged from health facilities in western Kenya.
METHODS
Between June 2016 and November 2019, children aged 1 to 59 months were enrolled at the point of discharge from the hospital. was isolated by microbiological culture from rectal swabs at baseline. β-Lactamases and macrolide resistance-conferring genes were detected by polymerase chain reaction. A modified Poisson regression model was used to assess the predictors (A) and CTX-M-type extended-spectrum β-lactamase (ESBL).
RESULTS
Of the 238 children whose isolates were tested, 91 (38.2%) and 109 (45.8%) had detectable CTX-M-type ESBL and (A) genes, respectively. Antibiotic treatment during hospitalization (adjusted prevalence ratio [aPR], 2.47; 95% CI, 1.12-5.43; = .025), length of hospitalization (aPR, 1.42; 95% CI, 1.00-2.01; = .052), and the practice of open defecation (aPR, 2.47; 95% CI, 1.40-4.36; = .002) were independent predictors for CTX-M-type ESBL and (A) genes. Pneumococcal vaccination was associated with a 43% lower likelihood of CTX-M-type ESBL (aPR, 0.57; 95% CI, .38-.85; = .005), while measles vaccination was associated with a 32% lower likelihood of (A) genes (aPR, 0.68; 95% CI, .49-.93; = .017) in isolates.
CONCLUSIONS
Among children discharged from the hospital, history of vaccination, shorter hospital stay, lack of in-hospital antibiotic exposure, and improved sanitation were associated with a lower likelihood of AMR genes. To mitigate the continued spread of AMR, AMR control programs should consider strategies beyond antimicrobial stewardship, including improvements in sanitation, increased vaccine coverage, and the development of novel vaccines.
PubMed: 38938894
DOI: 10.1093/ofid/ofae307 -
Science (New York, N.Y.) Jun 2024An intermediate virus-cell fusion step is revealed by an antibody with therapeutic potential.
An intermediate virus-cell fusion step is revealed by an antibody with therapeutic potential.
Topics: Measles virus; Virus Internalization; Humans; Antibodies, Viral; Measles; Animals; Antibodies, Neutralizing; Antibodies, Monoclonal
PubMed: 38935737
DOI: 10.1126/science.adq3348 -
Science (New York, N.Y.) Jun 2024Measles virus (MeV) presents a public health threat that is escalating as vaccine coverage in the general population declines and as populations of immunocompromised...
Measles virus (MeV) presents a public health threat that is escalating as vaccine coverage in the general population declines and as populations of immunocompromised individuals, who cannot be vaccinated, increase. There are no approved therapeutics for MeV. Neutralizing antibodies targeting viral fusion are one potential therapeutic approach but have not yet been structurally characterized or advanced to clinical use. We present cryo-electron microscopy (cryo-EM) structures of prefusion F alone [2.1-angstrom (Å) resolution], F complexed with a fusion-inhibitory peptide (2.3-Å resolution), F complexed with the neutralizing and protective monoclonal antibody (mAb) 77 (2.6-Å resolution), and an additional structure of postfusion F (2.7-Å resolution). In vitro assays and examination of additional EM classes show that mAb 77 binds prefusion F, arrests F in an intermediate state, and prevents transition to the postfusion conformation. These structures shed light on antibody-mediated neutralization that involves arrest of fusion proteins in an intermediate state.
Topics: Antibodies, Neutralizing; Measles virus; Cryoelectron Microscopy; Viral Fusion Proteins; Antibodies, Monoclonal; Antibodies, Viral; Humans; Protein Conformation
PubMed: 38935733
DOI: 10.1126/science.adm8693 -
Military Medicine Jun 2024During the coronavirus disease of 2019 (COVID-19) pandemic, routine childhood immunization rates dropped dramatically across the world, and the Military Health System...
INTRODUCTION
During the coronavirus disease of 2019 (COVID-19) pandemic, routine childhood immunization rates dropped dramatically across the world, and the Military Health System (MHS) was no exception. In the MHS, which is a large, universally covered, low-to-no-cost health system, the immunization rates with the measles, mumps, and rubella (MMR) vaccine remain below the rate necessary to prevent community transmission of measles. We aimed to improve childhood immunization rates in the MHS with an expansive quality improvement project.
MATERIALS AND METHODS
Measles, mumps, and rubella immunization rates served as proxy outcome measures for routine immunization rates tracked by the Center for Disease Control multi-immunization combination measures. The tracked measure was the percentage of 16- to 18-month olds and 6-year olds who had received MMR #1 and MMR #2, respectively. Various countermeasures were implemented throughout the study period, and standard quality improvement analyses informed the effect of countermeasures.
RESULTS
By January 2023, the percentage of 16- to 18-month olds and 6-year olds who had received MMR #1 and MMR #2 was 85% and 91%, respectively, with no positive shift in immunization rates despite various countermeasures introduced during the study period. For reference, the MMR immunization rates of commercial health maintenance organization and commercial preferred provider organization for 24-month-old populations were 92% and 90.3%, respectively. On chart review, the most common cause for under-immunization (55%) was vaccine abandonment. MMR #1 rates rose to 92% in 24-month olds.
CONCLUSIONS
Measles, mumps, and rubella immunization rates within the MHS remained below commercial health system rates and below public health standards required for herd immunity despite various countermeasures throughout the COVID-19 pandemic. Immunization rates increased with age, suggesting that children within the MHS eventually catch up despite potential barriers.
PubMed: 38935398
DOI: 10.1093/milmed/usae323 -
Vaccines Jun 2024No vaccine has been more effective in reducing disease burden, especially in preventing child deaths, than measles-containing vaccine. The return on investment makes...
No vaccine has been more effective in reducing disease burden, especially in preventing child deaths, than measles-containing vaccine. The return on investment makes measles-containing vaccine one of the most cost-effective public health measures available. Exhaustive reviews of biological, technical, economic and programmatic evidence have concluded that measles can and should be eradicated, and by including rubella antigen in measles-containing vaccine, congenital rubella syndrome will also be eradicated. All World Health Organisation Regions have pledged to achieve measles elimination. Unfortunately, not all countries and global partners have demonstrated an appropriate commitment to these laudable public health goals, and the negative impact of the COVID-19 pandemic on coverage rates has been profound. Unsurprisingly, large disruptive outbreaks are already occurring in many countries with a global epidemic curve ominously similar to that of 2018/2019 emerging. The Immunization Agenda 2030 will fail dismally unless measles and rubella eradication efforts are accelerated. Over half of all member states have been verified to have eliminated rubella and endemic rubella transmission has not been re-established in any country to date. In 2023, 84 countries and areas were verified to have sustained elimination of measles. However, without a global target, this success will be difficult to sustain. Now is the time for a global eradication goal and commitment by the World Health Assembly. Having a galvanising goal, with a shared call for action, will demand adequate resourcing from every country government and global partners. Greater coordination across countries and regions will be necessary. Measles, rubella and congenital rubella syndrome eradication should not remain just a technically feasible possibility but rather be completed to ensure that future generations of children do not live under the shadow of preventable childhood death and lifelong disability.
PubMed: 38932428
DOI: 10.3390/vaccines12060699 -
Vaccines Jun 2024I am delighted and honored to be Guest Editor of this Special Issue on measles and rubella elimination [...].
I am delighted and honored to be Guest Editor of this Special Issue on measles and rubella elimination [...].
PubMed: 38932427
DOI: 10.3390/vaccines12060698 -
Vaccines Jun 2024Measles and rubella are vaccine-preventable viral diseases and can be prevented by safe, highly effective vaccination with measles- and rubella-containing vaccines.... (Review)
Review
Measles and rubella are vaccine-preventable viral diseases and can be prevented by safe, highly effective vaccination with measles- and rubella-containing vaccines. Given the myriad causes of febrile exanthems, laboratory surveillance for both measles and rubella is important to document the incidence of these diseases and to track the progress and maintenance of elimination in near- and post-elimination settings. Diagnostic challenges can hinder effective surveillance and classification challenges can hinder efforts to demonstrate achievement or maintenance of elimination. In this report, we review diagnostic and classification challenges for measles and rubella in near- and post-elimination settings.
PubMed: 38932426
DOI: 10.3390/vaccines12060697 -
Vaccines Jun 2024Mongolia experienced a nationwide measles outbreak during 1 March 2015-31 December 2016, with 49,077 cases reported to the WHO; many were among vaccinated young adults,...
Mongolia experienced a nationwide measles outbreak during 1 March 2015-31 December 2016, with 49,077 cases reported to the WHO; many were among vaccinated young adults, suggesting a possible role of vaccine failure. Advanced laboratory methods, coupled with detailed epidemiological investigations, can help classify cases as vaccine failure, failure to vaccinate, or both. In this report, we conducted a study of cases to identify risk factors for breakthrough infection for a subset of laboratory-confirmed measles cases. Of the 193 cases analyzed, only 19 (9.8%) reported measles vaccination history, and 170 (88%) were uncertain. Measles-specific IgG avidity testing classified 120 (62%) cases as low IgG avidity, indicating no prior exposure to measles. Ten of these cases with low IgG avidity had a history of measles vaccination, indicating primary vaccine failure. Overall, sixty cases (31%) had high IgG avidity, indicating breakthrough infection after prior exposure to measles antigen through vaccination or natural infection, but the IgG avidity results were highly age-dependent. This study found that among young children aged 9 months-5 years, breakthrough infection was rare (4/82, 5%); however, among young adults aged 15-25 years, breakthrough infection due to secondary vaccine failure (SVF) occurred on a large scale during this outbreak, accounting for the majority of cases (42/69 cases, 61%). The study found that large-scale secondary vaccine failure occurred in Mongolia, which highlights the potential for sustained outbreaks in post-elimination settings due to "hidden" cohorts of young adults who may have experienced waning immunity. This phenomenon may have implications for the sustainability of measles elimination in countries that remain vulnerable to the importation of the virus from areas where it is still endemic. Until global measles elimination is achieved, enhanced surveillance and preparedness for future outbreaks in post- or peri-elimination countries may be required.
PubMed: 38932425
DOI: 10.3390/vaccines12060695