Widespread Delivery Research Articles

DDEL-01. ENGINEERING MRNA THERAPIES FOR BRAIN TUMORS

Abstract Safe delivery of mRNA to the brain will revolutionize the treatment of brain tumors. While lipid nanoparticles (LNPs) are clinically most advanced non-viral delivery vehicles for therapeutic mRNA, LNP-mediated mRNA delivery to the brain remains challenging. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain cells without undue toxicity. We engineered LNPs consisting of four components similar to the formulation used in the mRNA COVID-19 vaccines (Moderna and Pfizer-BioNTech): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. We screened ten classes of helper lipids based on lipids enriched in extracellular vesicles to engineer biomimetic LNPs and tested their GFP mRNA delivery efficacy in SIM-A9 mouse microglia cell line. Several unique LNP formulations with potent delivery efficacy (>90% cells transfected) and stable GFP expression kinetics (5 days) were identified. LNP formulations with high transfection efficacy were then tested in vivo for luciferase mRNA delivery via intrathecal injection in C57BL/6 mice. Luciferase expression in vivo confirmed widespread mRNA delivery in the brain. We then tested Cre recombinase mRNA delivery in Ai9 mouse to identify LNP-targeted cells via flow cytometry and histology. Flow cytometry and expansion microscopy confirmed Cre recombinase mRNA delivery to a variety of brain cells, including microglia (75-90%), neurons (31-40%), neural stem cells (39-62%), oligodendrocytes (70-90%), and astrocytes (44-76%). LNPs were further evaluated for Cas9 mRNA and CD81 sgRNA delivery in C57BL/6 mouse brains to assess brain-targeted gene editing. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~40% of cells in the mouse brain. In summary, we engineered extracellular vesicle-based LNP library that can deliver RNA therapeutics to a variety of brain cells in vivo. With further development, this technology could potentially enable genetic and epigenetic therapies targeting drivers of brain tumors.

Forensic intelligence in Australia and New Zealand: Status and future directions

Forensic science is underutilised. Operating models restricted to the support of court outcomes do not address core requirements of contemporary policing and public security, which are to disrupt criminal activity and prevent crime. Forensic intelligence (FORINT) is a principal means of enhancing the role of forensic science, emphasising proactivity and cross-case, cross-crime domain insights. To catalyse implementation, a FORINT Specialist Advisory Group (SAG) has been established under the Australia & New Zealand Policing Advisory Agency (ANZPAA) National Institute of Forensic Science (NIFS). The SAG has established a concept of operations with four lines of effort – namely, to (i) promote awareness and consistency, (ii) shape the workforce, (iii) develop information management frameworks and (iv) guide operational implementation. This aims to shift Australia & New Zealand from its present state (of substantial interagency variability) to a state of widespread, consistent and effective FORINT delivery in terms of: (a) culture, (b) information management, (c) education & training, and (d) organisation & operating environment. There are risks to implementing FORINT, in terms of privacy/confidentiality, bias/misinterpretation, and resource impost. However, these are not necessarily FORINT-specific, and solutions or mitigations exist. Moreover, these issues are outweighed by the risks of not implementing FORINT – such as a failure to reveal threats, missed opportunities, and poor resource efficiency. This paper is a call to arms. For policing and laboratories – now is the time to implement and entrench FORINT. For academia – now is the time to build foundations for this future. For supporting industries – now is the time to develop partnerships and facilitate delivery.

Scalable microfluidic method for tunable liposomal production by a design of experiment approach

Liposomes constitute a widespread drug delivery platform, gaining more and more attention from the pharmaceutical industry and process development scientists. Their large-scale production as medicinal products for human use is all but trivial, especially when parenteral administration is required. In this study an off-the-shelf microfluidic system and a methodological approach are presented for the optimization, validation and scale-up of highly monodisperse liposomes manufacturing. Starting from a Doxil®-like formulation (HSPC, MPEG-DSPE and cholesterol), a rational approach (Design of Experiments, DoE) was applied for the screening of the process parameters affecting the quality attributes of the product (mainly size and polydispersity). Additional DoEs were conducted to determine the effect of critical process parameters “CPPs” (cholesterol concentration, total flow rate “TFR” and flow rate ratio “FRR”), thus assessing the formulation and process robustness. A scale-up was then successfully accomplished. The procedure was applied to a Marqibo®-like formulation as well (sphingomyelin and cholesterol) to show the generality of the proposed formulation, process development and scale-up approach. The application of the system and method herein presented enables the large-scale manufacturing of liposomes, in compliance with the internationally recognized regulatory standards for pharmaceutical development (Quality by Design).

Educate and Empower: An Online Intervention to Improve College Women’s Knowledge and Confidence When Communicating in a Romantic Relationship

Women provide the vast majority of unpaid family work, with deleterious associated outcomes including lost jobs, increased poverty, relationship dissatisfaction, and mental health concerns. Women’s unequal share of family work increased during the COVID-19 pandemic, and their mental health concerns were exacerbated. To prevent struggles with mental health and promote healthy communication and equal family work distribution, the PARTNERS communication model and an innovative online video intervention were created to teach college women about the importance of equitable family work distribution and healthy communication. Findings from this study suggested the PARTNERS intervention was effective in educating 303 undergraduate women about family work distribution, couple communication, and a model of effective communication, and improving college women’s confidence communicating with a romantic partner. Should these findings be replicated, the PARTNERS intervention may serve as a fiscally sustainable prevention model for future widespread service delivery to educate college women about family work distribution and effective communication and improve their confidence communicating with a romantic partner. Ultimately, this intervention may serve as a mechanism for social justice by contributing to the equalization of family work distribution, thus improving women’s relationship satisfaction and mental health.

Eligibility for antiamyloid treatment: preparing for disease-modifying therapies for Alzheimer’s disease

BackgroundDisease-modifying therapies (DMTs) for Alzheimer’s disease (AD) have early evidence of efficacy. Widespread delivery of DMTs will require major service reconfiguration. Treatment pathways will need to include triaging for eligibility,...

PIX is an N-terminal delivery domain that defines a class of polymorphic T6SS effectors in Enterobacterales

The type VI secretion system (T6SS), a widespread protein delivery apparatus, plays a role in bacterial competition by delivering toxic effectors into neighboring cells. Identifying new T6SS effectors and deciphering the mechanism that governs their secretion remain major challenges. Here, we report two orphan antibacterial T6SS effectors in the pathogen Pantoea agglomerans (Pa). These effectors share an N-terminal domain, Pantoea type six (PIX), that defines a widespread class of polymorphic T6SS effectors in Enterobacterales. We show that the PIX domain is necessary and sufficient for T6SS-mediated effector secretion and that PIX binds to a specialized Pa VgrG protein outside its C-terminal toxic domain. Our findings underline the importance of identifying and characterizing delivery domains in polymorphic toxin classes as a tool to reveal effectors and shed light on effector delivery mechanisms.

Psychedelic Therapy as Form of Life

In the historical context of a crisis in biological psychiatry, psychedelic drugs paired with psychotherapy are globally re-emerging in research clinics as a potential transdiagnostic therapy for treating mood disorders, addictions, and other forms of psychological distress. The treatments are poised to soon shift from clinical trials to widespread service delivery in places like Australia, North America, and Europe, which has prompted ethical questions by social scientists and bioethicists. Taking a broader view, we argue that the ethics of psychedelic therapy concerns not simply how psychotherapies are different when paired with psychedelic drugs, but how psychedelic therapies shape and are shaped by different values, norms, and metaphysical commitments. Drawing from the published literature and interviews with seven psychedelic therapists working in clinical trials in the United States, Germany, Switzerland, and Australia, this article opens the black box of the treatments to consider the values and informal debates currently animating the therapies. Considering questions of patient autonomy, mechanisms of therapeutic action, and which therapies are best suited to pair with psychedelic substances, we examine the ethics of psychedelic therapy as an emergent form of life. To bring this form of life out in fuller relief, we conclude by comparing and contrasting it with ayahuasca use in Amazonian shamanism.

Treatment of infantile-onset Pompe disease in a rat model with muscle-directed AAV gene therapy

ObjectivePompe disease (PD) is caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA), leading to progressive glycogen accumulation and severe myopathy with progressive muscle weakness. In the Infantile-Onset PD (IOPD), death generally occurs <1 year of age. There is no cure for IOPD. Mouse models of PD do not completely reproduce human IOPD severity. Our main objective was to generate the first IOPD rat model to assess an innovative muscle-directed adeno-associated viral (AAV) vector-mediated gene therapy. MethodsPD rats were generated by CRISPR/Cas9 technology. The novel highly myotropic bioengineered capsid AAVMYO3 and an optimized muscle-specific promoter in conjunction with a transcriptional cis-regulatory element were used to achieve robust Gaa expression in the entire muscular system. Several metabolic, molecular, histopathological, and functional parameters were measured. ResultsPD rats showed early-onset widespread glycogen accumulation, hepato- and cardiomegaly, decreased body and tissue weight, severe impaired muscle function and decreased survival, closely resembling human IOPD. Treatment with AAVMYO3-Gaa vectors resulted in widespread expression of Gaa in muscle throughout the body, normalizing glycogen storage pathology, restoring muscle mass and strength, counteracting cardiomegaly and normalizing survival rate. ConclusionsThis gene therapy holds great potential to treat glycogen metabolism alterations in IOPD. Moreover, the AAV-mediated approach may be exploited for other inherited muscle diseases, which also are limited by the inefficient widespread delivery of therapeutic transgenes throughout the muscular system.

A history of home mechanical ventilation: The past, present and future.

This state-of-the-art review provides an overview of the history of home mechanical ventilation (HMV), including early descriptions of mechanical ventilation from ancient and Renaissance perspectives and the mass development of ventilators designed for long-term use during the poliomyelitis epidemic. Seminal data from key clinical trials supports the application of HMV in certain patients with chronic obstructive pulmonary disease, neuromuscular disease and obesity-related respiratory failure. Innovative engineering coupled with refined physiological understanding now permits widespread delivery of home mechanical ventilation to a global population, using portable devices with advanced ventilatory modes and telemonitoring capabilities. Exponential growth in digital technology continues, and ongoing research is needed to understand how to harness clinical and physiological data to benefit patients and healthcare services in a clinically- and cost-effective manner.

Rapid and Widespread Distribution of Intranasal Small Extracellular Vesicles Derived from Mesenchymal Stem Cells throughout the Brain Potentially via the Perivascular Pathway.

Intranasal administration is a promising strategy to enhance the delivery of the sEVsomes-based drug delivery system to the central nervous system (CNS). This study aimed to explore central distributive characteristics of mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) and underlying pathways. Here, we observed that intranasal MSC-sEVs were rapidly distributed to various brain regions, especially in the subcortex distant from the olfactory bulb, and were absorbed by multiple cells residing in these regions. We captured earlier transportation of intranasal MSC-sEVs into the perivascular space and found an increase in cerebrospinal fluid influx after intranasal administration, particularly in subcortical structures of anterior brain regions where intranasal sEVs were distributed more significantly. These results suggest that the perivascular pathway may underlie the rapid and widespread central delivery kinetics of intranasal MSC-sEVs and support the potential of the intranasal route to deliver MSC-sEVs to the brain for CNS therapy.

Tackling implicit and explicit stigma towards voice hearing in clinical psychology students before it enters the workplace: a preliminary brief educational intervention

ABSTRACT Objective Hearing voices is a highly stigmatised experience, despite being common across clinical and non-clinical populations. The stigma held by healthcare professions of the clinical populations they work with can have a detrimental impact on the recovery trajectory of people with mental illness, with early career professionals and students thought to have among the most negative attitudes. Method The current study examined the efficacy of an education intervention to reduce implicit and explicit stigma surrounding voice hearing in psychology students (N = 49). With the world turning to digital delivery methods in the face of COVID-19, the study also examined the impact of intervention delivery mode: comparing online with face-to-face delivery. Results Results indicated that the education intervention was associated with improvements to explicit – but not implicit – stigma towards voice hearing. Comparisons between education delivery type suggested online and face-to-face delivery methods found no difference in associated reductions to explicit stigma. Conclusions These findings provide further support for the use of education interventions to reduce stigma surrounding voice hearing and support the online administration of such interventions to allow for more widespread education delivery to a broader audience.

Developing a single-session strategy for the implementation of take-home naloxone by community pharmacists using COM-B and design-thinking.

Despite the overwhelming evidence of its effectiveness, there is poor implementation of take-home naloxone by pharmacists. Barriers have been explored and mapped to the capability, opportunity, motivation-behaviour (COM-B) model of behaviour change, yet no theoretically informed implementation strategies that target known barriers have been developed. Single-session implementation strategies have been proposed as a simple, scalable way to target multiple barriers. Qualitative participatory methods, incorporating design-thinking principles, were used to develop the key messages of a single-session implementation strategy. The key messages were drafted against COM-B mapped implementation barriers identified in the literature. A participatory workshop involving a pre-mortem exercise and incorporating design-thinking principles were used to refine the messages and generate methods for dissemination. Messages were mapped to interview questions to naturally illicit stories and delivered via storytelling from a pharmacist, a general practitioner, and a person with lived experience of using naloxone. A 3 minute 40 second video and a two-page printable infographic were developed and hosted on a website, with links to additional downloadable resources as a single-session implementation strategy. Email was the preferred method for receiving simple professional development communications, with social media also widely accessed. Implementation science, behavioural change theory, and participatory design methods are a complementary combination to develop implementation strategies. Some pharmacists questioned the participatory design approach to developing an implementation strategy, as it was outside of their comfort zone. However, the participatory process involving end-users resulted in unique ideas that are unlikely to have been generated using more traditional consultative approaches. The delivery as a single-session implementation strategy allows for widespread dissemination and delivery at scale.

VWA3A-derived ependyma promoter drives increased therapeutic protein secretion into the CSF

Recombinant adeno-associated viral vectors (rAAVs) are a promising strategy to treat neurodegenerative diseases because of their ability to infect non-dividing cells and confer long-term transgene expression. Despite an ever-growing library of capsid variants, widespread delivery of AAVs in the adult central nervous system remains a challenge. We have previously demonstrated successful distribution of secreted proteins by infection of the ependyma, a layer of post-mitotic epithelial cells lining the ventricles of the brain and central column of the spinal cord, and subsequent protein delivery via the cerebrospinal fluid (CSF). Here we define a functional ependyma promoter to enhance expression from this cell type.Using RNA sequencing on human autopsy samples, we identified disease- and age-independent ependyma gene signatures. Associated promoters were cloned and screened aslibraries in mouse and rhesus macaque to reveal cross-species function of a human DNA-derived von Willebrand factordomain containing 3A (VWA3A) promoter. When tested in mice, our VWA3A promoter drove strong, ependyma-localized expression of eGFP and increased secreted ApoE protein levels in the CSF by 2-12× over the ubiquitous iCAG promoter.

Preventive health care in blood cancer survivors: results from the ABC study

BackgroundBlood cancer survivors are at increased risk for second primary malignancies, cardiovascular diseases, and infections. Little is known about preventive care in blood cancer survivors.MethodsOur questionnaire-based study included blood cancer patients diagnosed at the University Hospital of Essen before 2010, with a ≥ 3-year interval from the last intense treatment. One section of the retrospective study covered preventive care (cancer screening, cardiovascular screening, vaccination).ResultsPreventive care was delivered by a general practitioner for 1100 of 1504 responding survivors (73.1%), by an oncologist for 125 (8.3%), by a general practitioner together with an oncologist for 156 (10.4%), and by other disciplines for 123 (8.2%). Cancer screening was more consistently performed by general practitioners than by oncologists. The converse was true for vaccination, with particularly high vaccination rates in allogeneic transplant recipients. Cardiovascular screening did not differ between care providers. Cancer and cardiovascular screening rates in survivors eligible for statutory prevention programs were higher than in the general population (skin cancer screening 71.1%; fecal occult blood testing 70.4%; colonoscopy 64.6%; clinical breast examination 92.1%; mammography 86.8%; cervical smear 86.0%; digital rectal examination 61.9%; blood pressure test 69.4%; urine glucose test 54.4%; blood lipid test 76.7%; information about overweight 71.0%). The Streptococcus pneumoniae vaccination rate was higher (37.0%) and the influenza vaccination rate was lower (57.0%) than in the general population.ConclusionsUtilization of preventive care is high among German blood cancer survivors. To ensure widespread delivery and avoid redundancy, communication between oncologists and preventive care providers is essential.

Barriers and facilitators to implementing the Veterans Health Administration National Teleoncology Service: A qualitative descriptive study.

e13684 Background: Many Veterans lack local access to specialized cancer services. When timely VA care is not accessible, the VA covers the cost of care provided in a Veteran’s community. This benefit disrupts integrated care delivery within VA and may be less applicable for Veterans in areas where specialized cancer services may also not be available locally. The National TeleOncology (NTO) service was established to provide remotely delivered cancer services and increase access for Veterans to specialized cancer care. We sought to understand early implementation experiences as part of an ongoing evaluation of the VA National TeleOncology (NTO) service. Methods: Informed by the Consolidated Framework for Implementation Research (CFIR), we conducted a qualitative descriptive study using virtual individual interviews with Veterans (results not reported) and focus groups with clinicians. To identify and describe implementation barriers and facilitators, oncologists, nurse practitioners (NPs), and registered nurses (RNs) who provide care via teleoncology were asked about the need for NTO, its advantages/disadvantages compared to alternatives, and how to operationalize and measure NTO’s success. Additionally, Veterans who have participated in the teleoncology program were asked about their experiences; the analysis of this data is ongoing. We employed a team-based, rapid qualitative analysis using structured forms for notetaking. Theme matrix techniques facilitated data analysis and presentation. Findings were mapped to CFIR domains and constructs. Results: Guided by information power, we conducted 15 individual interviews with Veterans and three focus groups, separated by clinician type. The individual interviews lasted approximately 36 minutes, and focus groups lasted approximately 30 minutes. Most Veteran participants were male (87%), white (60%), and had prostate cancer (47%). Results from our analysis suggest that clinicians feel there are key challenges/barriers to engaging NTO: 1) can delay care; 2) perception that NTO may not be as personable as in-person care; 3) technology access/use can be difficult for some Veterans. They also reported key advantages/facilitators: 1) provides Veterans nationwide with accessibility to cancer specialists; 2) keeps patients in VA system to support better care coordination and team-based care that expedites needed follow-up services. Conclusions: Those involved in implementing NTO feel supported and that it works well overall, especially to provide better coordinated cancer care for Veterans. These data will support an ongoing NTO evaluation. Separate data collection efforts are underway to understand the quality of care delivered to inform the widespread scale-out and delivery of NTO.

Acute Kidney Injury Survivor Care Following Hospital Discharge: A Mixed-Methods Study of Nephrologists and Primary Care Providers.

Widespread delivery of high-quality care for acute kidney injury (AKI) survivors after hospital discharge requires a multidisciplinary team. We aimed to compare management approaches between nephrologists and primary care providers (PCPs) and explored strategies to optimize collaboration. Explanatory sequential mixed-methods study using a case-based survey followed by semi-structured interviews. Nephrologists and PCPs providing AKI survivor care at 3 Mayo Clinic sites and the Mayo Clinic Health System were included. Survey questions and interviews elucidated participants' recommendations for post-AKI care. Descriptive statistics were used to summarize survey responses. Qualitative data analysis used deductive and inductive strategies. A connecting and merging approach was used for mixed-methods data integration. 148 of 774 (19%) providers submitted survey responses (24/72 nephrologists and 105/705 PCPs). Nephrologists and PCPs recommended laboratory monitoring and follow-up with a PCP shortly after hospital discharge. Both indicated that the need for nephrology referral, and its timing should be dictated by clinical and non-clinical patient-specific factors. There were opportunities for improvement in medication and comorbid condition management in both groups. Incorporation of multidisciplinary specialists (eg, pharmacists) was recommended to expand knowledge, optimize patient-centered care, and alleviate provider workload. Survey findings may have been affected by non-response bias and the unique challenges facing clinicians and health systems during the COVID-19 pandemic. Participants were from a single health system, and their views or experiences may differ from those in other health systems or serving different populations. A multidisciplinary team-based model of post-AKI care may facilitate implementation of a patient-centered care plan, improve adherence to best practices, and reduce clinician and patient burden. Individualizing care for AKI survivors based on clinical and non-clinical patient-specific factors is needed to optimize outcomes for patients and health systems.

TDP-43 pathology and functional deficits in wild-type and ALS/FTD mutant cyclin F mouse models.

Amyotrophic lateral sclerosis (ALS) is characterised by a progressive loss of upper and lower motor neurons leading to muscle weakness and eventually death. Frontotemporal dementia (FTD) presents clinically with significant behavioural decline. Approximately 10% of cases have a known family history, and disease-linked mutations in multiple genes have been identified in FTD and ALS. More recently, ALS and FTD-linked variants have been identified in the CCNF gene, which accounts for an estimated 0.6% to over 3% of familial ALS cases. In this study, we developed the first mouse models expressing either wild-type (WT) human CCNF or its mutant pathogenic variant S621G to recapitulate key clinical and neuropathological features of ALS and FTD linked to CCNF disease variants. We expressed human CCNF WT or CCNFS621G throughout the murine brain by intracranial delivery of adeno-associated virus (AAV) to achieve widespread delivery via somatic brain transgenesis. These mice developed behavioural abnormalities, similar to the clinical symptoms of FTD patients, as early as 3months of age, including hyperactivity and disinhibition, which progressively deteriorated to include memory deficits by 8months of age. Brains of mutant CCNF_S621G mice displayed an accumulation of ubiquitinated proteins with elevated levels of phosphorylated TDP-43 present in both CCNF_WT and mutant CCNF_S621G mice. We also investigated the effects of CCNF expression on interaction targets of CCNF and found elevated levels of insoluble splicing factor proline and glutamine-rich (SFPQ). Furthermore, cytoplasmic TDP-43 inclusions were found in both CCNF_WT and mutant CCNF_S621G mice, recapitulating the key hallmark of FTD/ALS pathology. In summary, CCNF expression in mice reproduces clinical presentations of ALS, including functional deficits and TDP-43 neuropathology with altered CCNF-mediated pathways contributing to the pathology observed.

A polymeric nanocarrier that eradicates breast cancer stem cells and delivers chemotherapeutic drugs

BackgroundDrug nanocarriers can markedly reduce the toxicities and side effects of encapsulated chemotherapeutic drugs in the clinic. However, these drug nanocarriers have little effect on eradicating breast cancer stem cells (BCSCs). Although compounds that can inhibit BCSCs have been reported, these compounds are difficult to use as carriers for the widespread delivery of conventional chemotherapeutic drugs.MethodsHerein, we synthesize a polymeric nanocarrier, hyaluronic acid-block-poly (curcumin-dithiodipropionic acid) (HA-b-PCDA), and explore the use of HA-b-PCDA to simultaneously deliver chemotherapeutic drugs and eradicate BCSCs.ResultsBased on molecular docking and molecular dynamics studies, HA-b-PCDA delivers 35 clinical chemotherapeutic drugs. To further verify the drug deliver ability of HA-b-PCDA, doxorubicin, paclitaxel, docetaxel, gemcitabine and camptothecin are employed as model drugs to prepare nanoparticles. These drug-loaded HA-b-PCDA nanoparticles significantly inhibit the proliferation and stemness of BCSC-enriched 4T1 mammospheres. Moreover, doxorubicin-loaded HA-b-PCDA nanoparticles efficiently inhibit tumor growth and eradicate approximately 95% of BCSCs fraction in vivo. Finally, HA-b-PCDA eradicates BCSCs by activating Hippo and inhibiting the JAK2/STAT3 pathway.ConclusionHA-b-PCDA is a polymeric nanocarrier that eradicates BCSCs and potentially delivers numerous clinical chemotherapeutic drugs.Graphical

Bioinspired oral delivery devices

Oral administration is a widespread and convenient drug delivery approach. However, oral delivery can be affected by the complex digestive tract environment, including irregular tissue morphology, the presence of digestive enzymes, mucus and mucosal barriers, and spatiotemporal variance in physiological parameters. These obstacles can prevent the oral delivery of many therapeutics. To overcome these challenges, oral delivery devices can be designed with bioinspired compositions, structures or functions to make more drugs available for oral administration. Various bioinspired oral delivery devices have been developed by harnessing biological materials and living microorganisms, or by imitating biological structures and functions. In this Review, we discuss the design and modification of bioinspired oral delivery devices, examining engineering strategies to target specific tissues and applications. We highlight how key bottlenecks in oral delivery can be addressed through bioinspired designs, concluding with an outlook on the remaining challenges towards the clinical translation of bioinspired oral delivery devices.

Strong peak immunogenicity but rapid antibody waning following third vaccine dose in older residents of care homes

Third-dose coronavirus disease 2019 vaccines are being deployed widely but their efficacy has not been assessed adequately in vulnerable older people who exhibit suboptimal responses after primary vaccination series. This observational study, which was carried out by the VIVALDI study based in England, looked at spike-specific immune responses in 341 staff and residents in long-term care facilities who received an mRNA vaccine following dual primary series vaccination with BNT162b2 or ChAdOx1. Third-dose vaccination strongly increased antibody responses with preferential relative enhancement in older people and was required to elicit neutralization of Omicron. Cellular immune responses were also enhanced with strong cross-reactive recognition of Omicron. However, antibody titers fell 21–78% within 100 d after vaccine and 27% of participants developed a breakthrough Omicron infection. These findings reveal strong immunogenicity of a third vaccine in one of the most vulnerable population groups and endorse an approach for widespread delivery across this population. Ongoing assessment will be required to determine the stability of immune protection.