Animal models for COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19), an emerging respiratory infection caused by the introduction of a novel coronavirus into humans late in 2019 (first detected in Hubei province, China). As of 18 September 2020, SARS-CoV-2 has spread to 215 countries, has infected more than 30 million people and has caused more than 950,000 deaths. As humans do not have pre-existing immunity to SARS-CoV-2, there is an urgent need to develop therapeutic agents and vaccines to mitigate the current pandemic and to prevent the re-emergence of COVID-19. In February 2020, the World Health Organization (WHO) assembled an international panel to develop animal models for COVID-19 to accelerate the testing of vaccines and therapeutic agents. Here we summarize the findings to date and provides relevant information for preclinical testing of vaccine candidates and therapeutic agents for COVID-19.

Fourth Controlled Human Infection Model (CHIM) meeting, CHIM regulatory issues, May 24, 2023.

Many aspects of Controlled Human Infection Models (CHIMs, also known as human challenge studies and human infection studies) have been discussed extensively, including Good Manufacturing Practice (GMP) production of the challenge agent, CHIM ethics, environmental safety in CHIM, recruitment, community engagement, advertising and incentives, pre-existing immunity, and clinical, immunological, and microbiological endpoints. The fourth CHIM meeting focused on regulation of CHIM studies, bringing together scientists and regulators from high-, middle-, and low-income countries, to discuss barriers and hurdles in CHIM regulation. Valuable initiatives for regulation of CHIMs have already been undertaken but further capacity building remains essential. The Wellcome Considerations document is a good starting point for further discussions.

Safety of Streptococcus pyogenes Vaccines: Anticipating and Overcoming Challenges for Clinical Trials and Post-Marketing Monitoring.

Streptococcus pyogenes (Strep A) infections result in a vastly underestimated burden of acute and chronic disease globally. The Strep A Vaccine Global Consortium's (SAVAC's) mission is to accelerate the development of safe, effective, and affordable S. pyogenes vaccines. The safety of vaccine recipients is of paramount importance. A single S. pyogenes vaccine clinical trial conducted in the 1960s raised important safety concerns. A SAVAC Safety Working Group was established to review the safety assessment methodology and results of more recent early-phase clinical trials and to consider future challenges for vaccine safety assessments across all phases of vaccine development. No clinical or biological safety signals were detected in any of these early-phase trials in the modern era. Improvements in vaccine safety assessments need further consideration, particularly for pediatric clinical trials, large-scale efficacy trials, and preparation for post-marketing pharmacovigilance.

IABS/CEPI platform technology webinar: Is it possible to reduce the vaccine development time?

The International Alliance for Biological Standardization and the Coalition for Epidemic Preparedness Innovations organized a joint webinar on the use of platform technologies for vaccine development. To tackle new emerging infectious diseases, including SARS-CoV-2, rapid response platforms, using the same basic components as a backbone, yet adaptable for use against different pathogens by inserting new genetic or protein sequences, are essential. Furthermore, it is evident that development of platform technologies needs to continue, due to the emerging variants of SARS-CoV-2. The objective of the meeting was to discuss techniques for platform manufacturing that have been used for COVID-19 vaccine development, with input from regulatory authorities on their experiences with, and expectations of, the platforms. Industry and regulators have been very successful in cooperating, having completed the whole process from development to licensing at an unprecedented speed. However, we should learn from the experiences, to be able to be even faster when a next pandemic of disease X occurs.

Development of new TB regimens: Harmonizing trial design, product registration requirements, and public health guidance.

Christian Lienhardt and colleagues discuss the importance of communication and coordination between regulators, researchers, and policy makers to ensure tuberculosis trials provide high-quality evidence for policy decisions.

Facilitating Antibacterial Drug Development in a Time of Great Need.

The continued development of new antibacterial drugs is critical to meet patient and public health needs. In this editorial, authors from the US Food and Drug Administration and European Medicines Agency reflect on the role of public-private partnerships and the development of clinical trials networks as agents to guide and perform quality studies of antibacterial drugs.

Bacteriophage therapy: a regulatory perspective.

Despite the recognized problem of antibiotic multidrug resistance, very few antibacterial agents with new mechanisms of action are under development. Bacteriophage therapy could offer one alternative strategy to mitigate this challenge. Although widely used throughout the 20th century in Eastern Europe and the former Soviet Union, this potential therapy has not yet been investigated according to rigorous scientific standards. This paper reports on a multistakeholder meeting held at the EMA, which outlined the existing regulatory framework to which such therapy should adhere and reviewed the current obstacles and shortcomings in scientific development for bacteriophage therapy.

Hollow Fiber System Model for Tuberculosis: The European Medicines Agency Experience.

The in vitro hollow fiber system model has been qualified by the European Medicines Agency as a methodology for use in support of selection and development of antituberculosis regimens. More data are expected to be generated in the future to further characterize its value.

Analysis of licensed over-the-counter (OTC) antibiotics in the European Union and Norway, 2012.

Antimicrobial resistance is recognised as a growing problem that seriously threatens public health and requires prompt action. Concerns have therefore been raised about the potential harmful effects of making antibiotics available without prescription. Because of the very serious concerns regarding further spread of resistance, the over-the-counter (OTC) availability of antibiotics was analysed here. Topical and systemic OTC antibiotics and their indications were determined across 26 European Union (EU) countries and Norway by means of a European survey. We identified a total of 48 OTC products containing 20 different single antibiotics and three antibiotic combinations as active substances, used mainly as topical preparations in short treatment courses. Given the relevance of these medicines and the increasing risk of antimicrobial resistance, it is important to limit the availability of OTC antibiotics and to monitor their use.

Myocarditis associated with COVID-19 vaccination.

Following the start of the COVID-19 vaccination campaign, the adverse events of myocarditis and pericarditis were linked mainly to mRNA COVID-19 vaccines by the regulatory authorities worldwide. COVID-19 vaccines have been administered to several million people and the risk of myocarditis post COVID-19 vaccination has been characterised in great detail. At the present time the research data available are scarce and there is still no clear understanding of the biological mechanism/s responsible for this disease. This manuscript provides a concise overview of the epidemiology of myocarditis and the most prominent mechanistic insights in the pathophysiology of the disease. Most importantly it underscores the needed next steps in the research agenda required to characterize the pathophysiology of this disease post-COVID-19 vaccination. Finally, it shares our perspectives and considerations for public health.

Loco-Regional Anesthesia for Pain Management in Robotic Thoracic Surgery.

Robotic thoracic surgery is a prominent minimally invasive approach for the treatment of various thoracic diseases. While this technique offers numerous benefits including reduced blood loss, shorter hospital stays, and less postoperative pain, effective pain management remains crucial to enhance recovery and minimize complications. This review focuses on the application of various loco-regional anesthesia techniques in robotic thoracic surgery, particularly emphasizing their role in pain management. Techniques such as local infiltration anesthesia (LIA), thoracic epidural anesthesia (TEA), paravertebral block (PVB), intercostal nerve block (INB), and erector spinae plane block (ESPB) are explored in detail regarding their methodologies, benefits, and potential limitations. The review also discusses the imperative of integrating these anesthesia methods with robotic surgery to optimize patient outcomes. The findings suggest that while each technique has unique advantages, the choice of anesthesia should be tailored to the patient's clinical status, the complexity of the surgery, and the specific requirements of robotic thoracic procedures. The review concludes that a multimodal analgesia strategy, potentially incorporating several of these techniques, may offer the most effective approach for managing perioperative pain in robotic thoracic surgery. Future directions include refining these techniques through technological advancements like ultrasound guidance and exploring the long-term impacts of loco-regional anesthesia on patient recovery and surgical outcomes in the context of robotic thoracic surgery.

Robotic surgery for thymic cysts: clinical features, management, and results of a multicentric study.

Thymic cysts are rare, radiological diagnosis is often incidental, and cysts seldom assume clinical relevance for symptoms of compression. Thymoma were occasionally found inside both complex and simple thymic cysts. Given the challenges in accurately clinical diagnosing and since the occasionally discovering of thymoma inside both complex and simple thymic cysts, the management of thymic cysts remains controversial. Advancements in surgical tools such as robotics, applied to thymic conditions, could potentially transform the approach to thymic cysts. We report one the largest multicentric series of thymic cysts surgically treated with robotic approach, focusing on preoperative findings and surgical results. Cases were gathered from three Italian thoracic surgery centers with homogeneous clinical practice, significant experience in thymic neoplasms, and thoracic robotic skilled. Surgical intervention was indicated for patients with radiological diagnosis of thymic cysts under the following circumstances: the presence of symptoms, concurrent myasthenia gravis, cysts growing in follow-up, and the complexity of the cyst with suspicion of neoplasm. Data were collected and matched according to postoperative and pathological features to identify potential prognostic factors. Population include 57 patients, 29/28 male/female ratio with mean age of 59.46 ± 11.67 years. The average size of the thymic cysts was 29.14 ± 24.53 ranged between 3 and 150 mm. All patients undergone CT scan and mean of values of density was 25.82 ± 11-82 Hounsfield. Surgical procedures were robotic approach in all case including total/extended thymectomy 35 (61.4%) and cyst resection/partial thymectomy 22 (38.6%). There were no mortality or recurrence. Major complications rate was 5.3%. No correlations were observed between preoperative features and complication. Pathological examination revealed microfoci of thymic tumor in four cases. Robot-assisted surgery for thymic cysts showed excellent early clinical outcomes with low rate of postoperative complications also in case of large lesion. Thymic cysts should not be underestimated due to the risk of coexistent thymic neoplasm.

Long-term outcome in vaccine-induced immune thrombocytopenia and thrombosis.

BACKGROUND: Rapid diagnosis and treatment has improved outcome of patients with vaccine-induced immune thrombocytopenia and thrombosis (VITT). However, after the acute episode, many questions on long-term management of VITT remained unanswered. OBJECTIVES: To analyze, in patients with VITT, the long-term course of anti-platelet factor 4 (PF4) antibodies; clinical outcomes, including risk of recurrent thrombosis and/or thrombocytopenia; and the effects of new vaccinations. METHODS: 71 patients with serologically confirmed VITT in Germany were enrolled into a prospective longitudinal study and followed for a mean of 79 weeks from March 2021 to January 2023. The course of anti-PF4 antibodies was analyzed by consecutive anti-PF4/heparin immunoglobulin G enzyme-linked immunosorbent assay and PF4-enhanced platelet activation assay. RESULTS: Platelet-activating anti-PF4 antibodies became undetectable in 62 of 71 patients (87.3%; 95% CI, 77.6%-93.2%). In 6 patients (8.5%), platelet-activating anti-PF4 antibodies persisted for >18 months. Five of 71 patients (7.0%) showed recurrent episodes of thrombocytopenia and/or thrombosis; in 4 of them (80.0%), alternative explanations beside VITT were present. After further COVID-19 vaccination with a messenger RNA vaccine, no reactivation of platelet-activating anti-PF4 antibodies or new thrombosis was observed. No adverse events occurred in our patients subsequently vaccinated against influenza, tick-borne encephalitis, varicella, tetanus, diphtheria, pertussis, and polio. No new thrombosis occurred in the 24 patients (33.8%) who developed symptomatic SARS-CoV-2 infection following recovery from acute VITT. CONCLUSION: Once the acute episode of VITT has passed, patients appear to be at low risk for recurrent thrombosis and/or thrombocytopenia.

Clinical and regulatory development strategies for Shigella vaccines intended for children younger than 5 years in low-income and middle-income countries.

Shigellosis causes considerable public health burden, leading to excess deaths as well as acute and chronic consequences, particularly among children living in low-income and middle-income countries (LMICs). Several Shigella vaccine candidates are advancing in clinical trials and offer promise. Although multiple target populations might benefit from a Shigella vaccine, the primary strategic goal of WHO is to accelerate the development and accessibility of safe, effective, and affordable Shigella vaccines that reduce mortality and morbidity in children younger than 5 years living in LMICs. WHO consulted with regulators and policy makers at national, regional, and global levels to evaluate pathways that could accelerate regulatory approval in this priority population. Special consideration was given to surrogate efficacy biomarkers, the role of controlled human infection models, and the establishment of correlates of protection. A field efficacy study in children younger than 5 years in LMICs is needed to ensure introduction in this priority population.

Attention for sex in COVID-19 trials: a review of regulatory dossiers.

An under-representation of women and a lack of sex-specific analyses in COVID-19 trials has been suggested. However, the higher number of men than women who are severely affected by COVID-19 and the restricted information in scientific publications may have biased these suggestions. Therefore, we evaluated sex proportionality and sex-specific efficacy and safety data in trials of COVID-19 treatments and vaccines using both publicly available regulatory documents and confidential documents used by regulators in their review of medicinal products. Included were two treatments (ie, remdesivir and dexamethasone) and four vaccines (ie, BNT162b2 mRNA (BioNTech/Pfizer), mRNA-1273 (Moderna), ChAdOx1-S (AstraZeneca) and Ad26.COV2-S (Janssen)) that received marketing authorisation by the European Commission at the time of the study conduct. An under-representation of women was shown in three of the nine data sets for one treatment (ie, remdesivir), but the proportion of women included was representative in each of the data sets for the other five products. This indicates that there is no structural under-representation of women in the COVID-19 trials. Currently, sex-specific efficacy data are available for five of the six assessed products and sex-specific safety data are available for half of the products only. It is important that this information will also be made available for the other products. There are only small differences in efficacy and safety between men and women which are likely to be of limited clinical relevance. Sex-specific efficacy information can generally be found in the publicly available regulatory documents other than the Summary of Product Characteristics, for which more awareness might be required.

Building the concept for WHO Evidence Considerations for Vaccine Policy (ECVP): Tuberculosis vaccines intended for adults and adolescents as a test case.

Currently, no formal mechanisms or systematic approaches exist to inform developers of new vaccines of the evidence anticipated to facilitate global policy recommendations, before a vaccine candidate approaches regulatory approval at the end of pre-licensure efficacy studies. Consequently, significant delays may result in vaccine introduction and uptake, while post-licensure data are generated to support a definitive policy decision. To address the uncertainties of the evidence-to-recommendation data needs and to mitigate the risk of delays between vaccine recommendation and use, WHO is evaluating the need for and value of a new strategic alignment tool: Evidence Considerations for Vaccine Policy (ECVP). EVCPs aim to fill a critical current gap by providing early (pre-phase 3 study design) information on the anticipated clinical trial and observational data or evidence that could support WHO and/or policy decision making for new vaccines in priority disease areas. The intent of ECVPs is to inform vaccine developers, funders, and other key stakeholders, facilitating stakeholder alignment in their strategic planning for late stage vaccine development. While ECVPs are envisaged as a tool to support dialogue on evidence needs between regulators and policy makers at the national, regional and global level, development of an ECVP will not preclude or supersede the independent WHO's Strategic Advisory Group of Experts on Immunization (SAGE) evidence to recommendation (EtR) process that is required for all vaccines seeking WHO policy recommendation. Tuberculosis (TB) vaccine candidates intended for use in the adolescent and adult target populations comprise a portfolio of priority vaccines in late-stage clinical development. As such, TB vaccines intended for use in this target population provide a 'test case' to further develop the ECVP concept, and develop the first WHO ECVP considerations guidance.

Antimicrobial multidrug resistance in the era of COVID-19: a forgotten plight?

BACKGROUND: Antimicrobial resistance (AMR) is a growing global problem to which the ongoing COVID-19 pandemic may further contribute. With resources deployed away from antimicrobial stewardship, evidence of substantial pre-emptive antibiotic use in COVID-19 patients and indirectly, with deteriorating economic conditions fuelling poverty potentially impacting on levels of resistance, AMR threat remains significant. MAIN BODY: In this paper, main AMR countermeasures are revisited and priorities to tackle the issue are re-iterated. The need for collaboration is stressed, acknowledging the relationship between human health, animal health and environment ("One Health" approach). Among the stated priorities, the initiative by the European Medicines Regulatory Network to further strengthen the measures in combatting AMR is highlighted. Likewise, it is asserted that other emerging health threats require global collaboration with the One Health approach offering a valuable blueprint for action. CONCLUSION: The authors stress the importance of an integrated preparedness strategy to tackle this public health peril.

Shaping EU medicines regulation in the post COVID-19 era.

The EU Medicines Regulatory Network (EMRN), comprised of the European Medicines Agency (EMA), the medicines regulatory authorities of the Member States and the European Commission (EC), is operating amid a complex crisis that has positioned regulators centre stage due to their key role in the development, approval and safety monitoring of vaccines and treatments for COVID-19. Here we consider the EMA's and EMRN's response to the pandemic and some of the early learnings that will help reshape medicines regulation in the post COVID-19 era. We also reflect on how some of these learnings will be formally followed up under revised EU legislation to extend EMA's mandate, reinforcing its role in crisis preparedness and response.