Should the world collaborate imminently to develop neglected live-attenuated vaccines for COVID-19?

The rapid spread of the Delta variant suggests that SARS-CoV-2 will likely be rampant for months or years and could claim millions of more lives. All the known vaccines cannot well defeat SARS-CoV-2 due to their limited efficacy and production efficiency, except for the neglected live-attenuated vaccines (LAVs), which could have a much higher efficacy and much higher production efficiency than other vaccines. LAVs, like messiahs, have defeated far more pathogenic viruses than other vaccines in history, and most current human vaccines for viral diseases are safe LAVs. LAVs can block completely infection and transmission of relevant viruses and their variants. They can hence inhibit the emergence of vaccine-escape and virulence-enhancing variants and protect immunologically abnormal individuals better in general. The safety of COVID-19 LAVs, which could save millions of more lives, can be solidly guaranteed through animal experiments and clinical trials. The safety of COVID-19 LAVs could be greatly enhanced with intramuscular or oral administration, or administration along with humanized neutralizing monoclonal antibodies. Together, extensive global collaboration, which can greatly accelerate the development of safe COVID-19 LAVs, is imminently needed.     

Neonatal immune function and inflammatory illnesses in later life: lessons to be learnt from the developing world?

With the emergence of allergic and autoimmune diseases in populations that have started to transit to a western lifestyle, there has been an increasing interest in the role of environmental factors modulating early immune function. Yet, most of the information concerning neonatal immune function has been derived from studies in westernized countries. We postulate that comparative studies of early immune development in children born under conditions that are typical for a westernized vs. that of a still more traditional setting will provide a crucial insight into the environmental‐driven immunological mechanisms that are responsible for the world‐wide rise in inflammatory disorders. In this review, we summarize the current understanding of early‐life immune function in humans in general and the literature on some major lifestyle factors that may influence neonatal immune function and potentially the risk for disease in later life. An understanding of the mechanisms of ‘prenatal/early‐life programming’ in populations living in traditional compared with modern societies is crucial to develop strategies to prevent a further rise in ‘western diseases’ such as allergic disorders. Indications exist that prenatal conditioning of the innate immune system by low‐grade inflammatory responses is key to inducing more tightly regulated postnatal adaptive immune responses. Cite this as: J. G. Lisciandro and A. H. J. van den Biggelaar, Clinical & Experimental Allergy, 2010 (40) 1719–1731.     

Game of “crowning” season 8: RAS and reproductive hormones in COVID-19 – can we end this viral series?

The outbreak of a newly identified coronavirus, the SARS-CoV-2 (alternative name 2019-nCoV), capable of jumping across species causing zoonosis with severe acute respiratory syndromes (SARS), has alerted authorities worldwide. Soon after the epidemic was first detected in the city of Wuhan in the Hubei Province of China, starting in late December 2019, the virus spread over multiple countries in different continents, being declared a pandemic by March 2020. The demographic characteristics of the infected patients suggest that age, sex, and comorbidities are predictive factors for the fatality of the infection. The mechanisms of viral entry into the human host cells seem to be in a close relationship with the mechanisms of regulating the renin-angiotensin system (RAS), which may explain the pathogenesis associated with the infection. This brings new insights into the possibilities of exploiting viral entry mechanisms to limit associated complications by means of enhancing the resistance of the infected patients using methods of regulating the RAS and strategies of modulating ACE2 expression. In this perspective article we exploit the mechanisms of COVID-19 pathogenesis based on the demographic characteristics of the infected patients reported in the recent literature and explore several approaches of limiting the initial steps of viral entry and pathogenesis based on viral interactions with ACE2 and RAS. We further discuss the implications of reproductive hormones in the regulation of the RAS and investigate the premise of using endocrine therapy against COVID-19.     

Has the COVID-19 pandemic wiped out the seasonality of outpatient antibiotic use and influenza activity? A time-series analysis from 2014 to 2021

ObjectiveTo assess the influence of the emergence of severe acute respiratory syndrome coronavirus 2 and the implementation of public health measures on the seasonality of outpatient antibiotic use and their possible association with the incidence of influenza.MethodsWe performed a time-series ecological study in 1516 primary care centres of Andalusia, Spain, comparing the coronavirus disease 2019 period (April 2020 to March 2021) with the 6 previous years. We assessed the number of packs and defined daily doses per 1000 inhabitants of antibacterials and key antibiotics commonly used for acute respiratory tract infections and the number of influenza-positive cases per 100 000 inhabitants. We calculated the correlation between variables and analyzed the seasonal patterns and differences in quarterly antibiotic use.ResultsFor all quarters, a significant correlation was observed between influenza activity and antibiotic use (Spearman's r = 0.94; p < 0.001). Before the pandemic period, both variables presented similar seasonal patterns. After the start of the pandemic, influenza activity was suppressed and the pattern of antibiotic use flattened into a straight line (R² = 0.96; p = 0.022) with a quarterly change of 3.9% (p = 0.007). Total antibiotic use and antibiotics used for treating acute respiratory tract infections showed significant reductions in all quarters compared to the previous year (p < 0.01).DiscussionThe coronavirus disease 2019 pandemic has strongly influenced the seasonality of antibiotic use in primary care. The decline in respiratory viruses, among which the influenza virus is a major player that may act as a proxy for general prevalence, is proposed as a reason for the flattening of the seasonal fluctuations of outpatient antibiotic use in our region.     

The COVID-19 pandemic and ANCA-associated vasculitis – reports from the EUVAS meeting and EUVAS education forum

The Coronavirus Disease 2019 (COVID-19) pandemic influenced the management of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. A paucity of data exists on outcome of patients with vasculitis following COVID-19, but mortality is higher than in the general population and comparable to patients undergoing haemodialysis or kidney transplant recipients (reported mortality rates of 20–25%). Delays in diagnosis have been reported, which are associated with sequelae such as dialysis-dependency. Management of ANCA-associated vasculitis has not changed with the aim to suppress disease activity and reduce burden of disease. The use of rituximab, an important and widely used agent, is associated with a more severe hospital course of COVID-19 and absence of antibodies following severe acute respiratory syndrome (SARS)-CoV-2 infections, which prone patients to re-infection. Reports on vaccine antibody response are scarce at the moment, but preliminary findings point towards an impaired immune response, especially when patients receive rituximab as part of their treatment. Seropositivity was reported in less than 20% of patients when rituximab was administered within the prior six months, and the antibody response correlated with CD19⁺ B-cell repopulation. A delay in maintenance doses, if disease activity allows, has been suggested using a CD19⁺ B-cell guided strategy. Other immunosuppressive measures, which are used in ANCA-associated vasculitis, also impair humoral and cellular vaccine responses. Regular measurements of vaccine response or a healthcare-policy time-based strategy are indicated to provide additional doses (“booster”) of COVID-19 vaccines. This review summarizes a recent educational forum and a recent virtual meeting of the European Vasculitis Society (EUVAS) focusing on COVID-19.     

What doubts,concerns and fears about COVID-19 emerged during the first wave of the pandemic?

ObjectivesThe control of the COVID-19 pandemic depends strongly on effective communication, which must be grounded on the population’s perceptions and knowledge. We aimed to analyse the doubts, concerns and fears expressed by the Portuguese population about COVID-19.MethodsWe performed a content analysis of 293 questions submitted to online, radio, newspaper and TV channel forums during the first month of the pandemic in Portugal.ResultsMost questions contained doubts (n = 230), especially on how to prevent person-to-person transmission (n = 40) and how to proceed in case of symptoms (n = 37). Concerns and fears were also very commonly expressed (n = 144), mostly about which persons could be considered vulnerable (n = 53) and how to prevent transmission during daily life or normal activities (n = 37).ConclusionAs the pandemic evolved and suppression measures were put in place, doubts moved to concerns of vulnerability, quarantine and social isolation, and to doubts about transmission, transmission prevention, and on how to proceed in case of symptoms.Practice implicationsThese results may inform future communication strategies for a more adequate response in the next phases of the COVID-19 pandemic, as well as in future pandemics.     

What can be learnt from the Japanese regulatory approach to tissue engineered products?

The Japanese government has recognized the challenges its rapidly aging population presents, especially in terms of healthcare provision, and is focusing on the potential of regenerative medicine to address them. The country has consequently embarked upon a national program to support development of this field. In 1999 Japan initiated a national research project in science and technology, known as the Millennium Project, whose areas of research include tissue engineering covering skin, cornea, bone, cartilage, blood vessels, nerves and bone marrow. In this context, at a time when regulations for tissue engineered products are being developed and revised in the USA and at the European level, it is interesting to investigate what type of framework Japanese regulators have designed to deal with these products in order to see what lessons might be learnt by UK, US and EU regulators. This paper reviews negative and positive aspects of the current regulatory situation that applies to tissue engineered products in Japan but will mostly focus on examples of good practice, such as the pragmatism that underpins the Japanese regulatory strategy, the international involvement of the country when it comes to developing regulatory standards and the promotion of a supportive public environment.     

Not as black as it is painted? The impact of the first wave of COVID-19 pandemic on surgical treatment of urological cancer patients in Poland – a cross-country experience

IntroductionIn the majority of Western European countries, the coronavirus disease (COVID-19) pandemic has led to a dramatic reduction in urooncological surgeries. Our objective was to evaluate the impact of the pandemic on volume and patterns of urooncological surgery in Poland.Material and methodsThis is a retrospective analysis of 10 urologic centres in Poland. Data regarding major oncological procedures performed after the COVID-19 pandemic outbreak (March 15, 2020 – May 31, 2020) were evaluated and compared with data from the respective period in 2019.ResultsBetween March 15, 2020 and May 31, 2020, a total of 968 oncological procedures were performed in participating centres. When compared to the respective period in 2019 (1063 procedures) the overall number of surgeries declined by 8.9%. The reduction was observed for transurethral resection of bladder tumour (TURBT) (20.1%) and partial nephrectomies (PN) (16.5%). Surgical activity considering radical nephrectomy (RN), nephroureterectomy (NU), and radical prostatectomy (RP) remained relatively unchanged, whereas radical cystectomy (RC) burden showed a significant increase (90.9%). Characteristics of patients treated with TURBT, RC, NU, PN, and RN did not differ significantly between the compared periods, whereas RP in the COVID-19 period was performed more frequently in patients with a higher grade group (p = 0.028) and positive digital rectal examination (p = 0.007).ConclusionsSurgical activity for urological cancers in Poland has been maintained during the first wave of the COVID-19 pandemic. The Polish strategy in the initial period of the COVID-19 crisis mirrors the scenario of hard initial lockdown followed by adaptive lockdown, during which oncological care remained undisrupted and did not require particular priority triage.     

Why Have the Republic of Korea,Taiwan, and Singapore Coped Well with COVID-19 and What Are the Lessons Learned from Their Experiences?

This study investigated how three Asian countries–Republic of Korea (ROK), Republic of China (Taiwan), and Singapore–considered as standouts, responded to the coronavirus disease 2019 (COVID-19) in terms of governance system, health sector innovation, and social distancing to draw lessons that other countries can learn from. The countries were commonly in success of the response in early stage of the pandemic thanks to their effective and efficient strategies paired with advanced information and communications technology (ICT). Consequently, the three jurisdictions reported lower confirmed cases as well as fatality rate of the infectious disease compared to other high-income countries. In addition, the countries’ previous experiences with other pandemics, including influenza A, Middle East respiratory syndrome, and severe acute respiratory syndrome, enabled them to establish resilient public health systems and gain public acceptance to governmental control or surveillance during national infectious disease-related crises outbreaks. Advanced ICT infrastructure and digital technology were used as effective tools for testing, tracing, and treatment of the pandemic in collaboration with the private sector as a crucial player. The ROK, Taiwan, and Singapore adopted different strategies between containment and mitigation policy to flatten the epidemic curves effectively according to their own situation and judgement. Despite the exemplary aspect of the three nations in coping with the COVID-19 pandemic, a few limitations were also observed in terms of vaccination and unequal consequences of the pandemic among people. These should be further discussed in order to be prepared for future pandemics.     

To be or Not to be Ridded? – That is the Question Addressed by the Associative Antigen Recognition Model*†

The reasons that germline-encoded recognitive sites cannot sort the immune system's large and random somatically generated repertoire into anti-Not-to-be-ridded ('self ') and anti-To-be-ridded ('nonself ') specificities are analysed. The immune system cannot use 'nonself '-markers of To-be-ridded antigens ('Danger', toll receptors, pathogenicity, localization, etc.) to sort the repertoire; it may, however, use them to determine the magnitude and class of the effector response.     

Induction of tolerance to hepatitis B virus: can we ‘eat the disease’ and live with the virus?

Hepatitis B virus (HBV) is a major health problem, with over 300 million HBsAg carriers worldwide. The HBV itself is non-cytopathic, and it is widely accepted that the mechanism of hepatocellular injury is the host anti-viral immune response. Current treatments, including the newly developed therapeutic modalities, are either based on anti-viral drugs or focus on attempts to augment the anti-viral immune response. The results of these approaches have been largely disappointing. There is evidence, however, that subjects with a natural tolerance to HBV or a down-regulated immune response develop little or no liver injury, despite chronic viremia. Lately, it has been shown that it is possible to induce tolerance toward viruses by oral administration of major viral structural proteins. Here, we discuss the pathogenesis of HBV-mediated liver disease and approaches to down-regulate the immune response directed against liver cells by orally inducing tolerance toward the virus. We hypothesize that this acquired tolerance should turn chronic active hepatitis patients with deteriorating disease into ‘healthy’ virus carriers. The proposed new treatment strategy would redirect the focus from augmenting anti-viral immune response to inducing host tolerance towards the virus.     

Managing uncertainty and responding to difficult emotions: Cancer patients’ perspectives on clinician response during the COVID-19 pandemic

ObjectivePatients undergoing cancer treatment during the COVID-19 pandemic have experienced stress and uncertainty with respect to disruptions in cancer care and COVID-19 related risks. We examined whether clinicians’ responsiveness to patients’ uncertainty and difficult emotions were associated with better health and well-being.MethodsPatients were recruited from cancer support communities and a market research firm. Respondents assessed clinicians communication that addressed uncertainty and difficult emotions. Health status measures included mental and physical health, coping during the pandemic, and psychological distress.Results317 respondents participated in the study. Patients’ perceptions of their clinicians responsiveness to patient uncertainty and negative emotions were associated with better mental health, physical health, coping, and less psychological distress (all p-values <0.001). Respondents with greater self-efficacy and social support also reported better health.ConclusionEven when controlling for patients’ personal and health-related characteristics, clinicians’ communication addressing patients’ uncertainty and difficult emotions predicted better health, better coping, and less psychological distress. Access to social support and self-efficacy also were associated with better health status.Practice implicationsClinicians’ communication focused on helping with uncertainty and difficult emotions is important to cancer patients, especially during the pandemic. Clinicians should also direct patients to resources for social support and patient empowerment.