In silico EsxG EsxH rational epitope selection: Candidate epitopes for vaccine design against pulmonary tuberculosis.

Rational design of new vaccines against pulmonary tuberculosis is imperative. Early secreted antigens (Esx) G and H are involved in metal uptake, drug resistance, and immune response evasion. These characteristics make it an ideal target for rational vaccine development. The aim of this study is to show the rational design of epitope-based peptide vaccines by using bioinformatics and structural vaccinology tools. A total of 4.15 µs of Molecular Dynamics simulations were carried out to describe the behavior in solution of heterodimer, single epitopes, and epitopes loaded into MHC-II complexes. In order to predict T and B cell epitopes for antigenic activation, bioinformatic tools were used. Hence, we propose three epitopes with the potential to design pulmonary tuberculosis vaccines. The possible use of the proposed epitopes includes subunit vaccines, as a booster in BCG vaccination to improve its immune response, as well as the generation of antibodies that interfere with the Mycobacterium tuberculosis homeostasis, affecting its survival.

Limited effect of reducing pulmonary tuberculosis incidence amid mandatory facial masking for COVID-19.

Although the incidence and mortality rates associated with tuberculosis (TB) have been decreasing in many countries, TB remains a major public health concern. Obligatory facial masking and reduced health-care capacity because of COVID-19 may substantially influence TB transmission and care. The Global Tuberculosis Report 2021 published by the World Health Organization indicated a TB rebound at the end of 2020, which coincided with the COVID-19 pandemic. We explored this rebound phenomenon in Taiwan by investigating whether TB incidence and mortality are affected by COVID-19 because of their common route of transmission. In addition, we investigated whether the incidence of TB varies across regions with different incidences of COVID-19. Data (2010-2021) regarding annual new cases of TB and multidrug-resistant TB were collected from the Taiwan Centers for Disease Control. TB incidence and mortality were assessed in Taiwan's seven administrative regions. Over the last decade, TB incidence decreased continually, even during 2020 and 2021, the years coinciding with the COVID-19 pandemic. Notably, TB incidence remained high in regions with low COVID-19 incidence. However, the overall decreasing trends of TB incidence and mortality remained unchanged during the pandemic. Facial masking and social distancing may prevent COVID-19 transmission but exhibit limited efficacy in reducing TB transmission. Thus, during health-related policymaking, policymakers must consider TB rebound, even in the post-COVID-19 era.

Incidence of pulmonary tuberculosis under the regular COVID-19 epidemic prevention and control in China.

BACKGROUND: The COVID-19 pandemic has driven public health intervention strategies, including keeping social distance, wearing masks in crowded places, and having good health habits, to prevent the transmission of the novel coronavirus (SARS-CoV-2). However, it is unknown whether the use of these intervention strategies influences morbidity in other human infectious diseases, such as tuberculosis. METHODS: In this study, three prediction models were constructed to compare variations in PTB incidences after January 2020 without or with intervention includes strict and regular interventions, when the COVID-19 outbreak began in China. The non-interventional model was developed with an autoregressive integrated moving average (ARIMA) model that was trained with the monthly incidence of PTB in China from January 2005 to December 2019. The interventional model was established using an ARIMA model with a continuing intervention function that was trained with the monthly PTB incidence in China from January 2020 to December 2020. RESULTS: Starting with the assumption that no COVID-19 outbreak had occurred in China, PTB incidence was predicted, and then the actual incidence was compared with the predicted incidence. A remarkable overall decline in PTB incidence from January 2020 to December 2020 was observed, which was likely due to the potential influence of intervention policies for COVID-19. If the same intervention strategy is applied for the next 2 years, the monthly PTB incidence would reduce on average by about 1.03 per 100,000 people each month compared with the incidence predicted by the non-interventional model. The annual incidence estimated 59.15 under regular intervention per 100,000 in 2021, and the value would decline to 50.65 with strict interventions. CONCLUSIONS: Our models quantified the potential knock-on effect on PTB incidence of the intervention strategy used to control the transmission of COVID-19 in China. Combined with the feasibility of the strategies, these results suggested that continuous regular interventions would play important roles in the future prevention and control of PTB.

Risk of infection associated with Janus Kinase (JAK) inhibitors and biological therapies in inflammatory intestinal disease and rheumatoid arthritis. Prevention strategies. / Riesgo de infección asociado a los inhibidores de las quinasas Janus (JAK) y las terapias biológicas en enfermedad inflamatoria intestinal y artritis reumatoide. Estrategias de prevención.

Patients with certain immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), have an increased risk of severe infectious diseases than the general population, which are mainly associated with the immunosuppressive treatments that they receive. These treatments act on the immune system through different mechanisms, causing different degrees of immunosuppression and a variable risk depending on whether the pathogen is a virus, bacteria or fungus. This article reviews the most relevant literature on the subject, which was selected and discussed by a panel of experts. The aim of this article is to review the risk of infections in patients with IBD and RA, and the potential preventive measures.

What did we learn from South Africa's first-ever tuberculosis prevalence survey?

The World Health Organization (WHO) has urged countries to conduct tuberculosis (TB) prevalence surveys to better understand the burden of TB and to enable the WHO to conduct global estimates. Until the report from the first-ever prevalence survey in South Africa (SA), the country had to rely on WHO estimates. The recently published report on the SA TB prevalence survey provides important estimates of the burden of TB disease as well as information on health-seeking behaviour. This review notes the key findings of the 2018 prevalence survey. The high prevalence of TB in SA continues to be a major cause for concern, and calls for a significantly improved response to reach the End TB targets set by the WHO.

In Vivo Antigen Expression Regulates CD4 T Cell Differentiation and Vaccine Efficacy against Mycobacterium tuberculosis Infection.

New vaccines are urgently needed against Mycobacterium tuberculosis (Mtb), which kills more than 1.4 million people each year. CD4 T cell differentiation is a key determinant of protective immunity against Mtb, but it is not fully understood how host-pathogen interactions shape individual antigen-specific T cell populations and their protective capacity. Here, we investigated the immunodominant Mtb antigen, MPT70, which is upregulated in response to gamma interferon (IFN-γ) or nutrient/oxygen deprivation of in vitro-infected macrophages. Using a murine aerosol infection model, we compared the in vivo expression kinetics of MPT70 to a constitutively expressed antigen, ESAT-6, and analyzed their corresponding CD4 T cell phenotype and vaccine protection. For wild-type Mtb, we found that in vivo expression of MPT70 was delayed compared to ESAT-6. This delayed expression was associated with induction of less differentiated MPT70-specific CD4 T cells but, compared to ESAT-6, also reduced protection after vaccination. In contrast, infection with an MPT70-overexpressing Mtb strain promoted highly differentiated KLRG1+CX3CR1+ CD4 T cells with limited lung-homing capacity. Importantly, this differentiated phenotype could be prevented by vaccination, and against the overexpressing strain, vaccination with MPT70 conferred protection similar to vaccination with ESAT-6. Together, our data indicate that high in vivo antigen expression drives T cells toward terminal differentiation and that targeted vaccination with adjuvanted protein can counteract this phenomenon by maintaining T cells in a protective less differentiated state. These observations shed new light on host-pathogen interactions and provide guidance on how future Mtb vaccines can be designed to tip the immune balance in favor of the host.IMPORTANCE Tuberculosis, caused by Mtb, constitutes a global health crisis of massive proportions and the impact of the current coronavirus disease 2019 (COVID-19) pandemic is expected to cause a rise in tuberculosis-related deaths. Improved vaccines are therefore needed more than ever, but a lack of knowledge on protective immunity hampers their development. The present study shows that constitutively expressed antigens with high availability drive highly differentiated CD4 T cells with diminished protective capacity, which could be a survival strategy by Mtb to evade T cell immunity against key antigens. We demonstrate that immunization with such antigens can counteract this phenomenon by maintaining antigen-specific T cells in a state of low differentiation. Future vaccine strategies should therefore explore combinations of multiple highly expressed antigens and we suggest that T cell differentiation could be used as a readily measurable parameter to identify these in both preclinical and clinical studies.

Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development.

Vaccine design traditionally focuses on inducing adaptive immune responses against a sole target pathogen. Considering that many microbes evade innate immune mechanisms to initiate infection, and in light of the discovery of epigenetically mediated innate immune training, the paradigm of vaccine design has the potential to change. The Bacillus Calmette-Guérin (BCG) vaccine induces some level of protection against Mycobacterium tuberculosis (Mtb) while stimulating trained immunity that correlates with lower mortality and increased protection against unrelated pathogens. This review will explore BCG-induced trained immunity, including the required pathways to establish this phenotype. Additionally, potential methods to improve or expand BCG trained immunity effects through alternative vaccine delivery and formulation methods will be discussed. Finally, advances in new anti-Mtb vaccines, other antimicrobial uses for BCG, and "innate memory-based vaccines" will be examined.

Tuberculosis among prisoners & health care workers.

TB in prisons and among HCW is a major public health concern in countries having high burden of disease. Prompt detection of TB is must in prisons by screening on entry, passive screening, mass screening and contact screening via clinical evaluation, smear microscopy and chest X-rays. The new rapid diagnostic methods - True-NAAT, CBNAAT and Line Probe Assay are important tools in the diagnosis. Implementation of effective preventive measures at every steps in various settings, along with airborne infection control and protective measures for staff must be ensured.

White paper on challenges and opportunities for TB elimination with focus on COVID & Post-COVID era developed through scientific roundtable resolutions at NATCON 2020.

A group of TB experts with vast clinical and epidemiological experience were drawn from a pool of doctors, epidemiologists and scientists participating in NATCON 2020 Conference in a closed-door session to discuss, highlight, and prioritize key resolutions that are most pertinent at present to eliminate TB from India and other developing countries in the Covid and post-COVID era. These Scientific experts were non-industry persons who met on 17th December, 2020 and used the prevailing scientific literature along with 2019 Joint Monitoring Mission document as a starting point of the discussion on this specific topic to build an agreement upon the resolutions. After the meeting on the virtual platform, all the attending doctors gave a set of recommendations on rebuilding TB Elimination programme in the Covid and Post-Covid era. Focused scientific roundtable discussion on rebuilding TB Elimination Post-Covid. Develop actionable recommendations for the scientific community and the government leadership to consider in moving forward. To prioritize the recommendations in the categories of Build-Prevent-Detect-Treat.

Opportunities from a new disease for an old threat: Extending COVID-19 efforts to address tuberculosis in South Africa.

The COVID-19 pandemic and phased nationwide lockdown have impacted negatively on individuals with tuberculosis (TB) and routine TB services. Through a literature review and the perspective of members of a national TB Think Tank task team, we describe the impact of the pandemic and lockdown on TB patients and services as well as the potential long-term setback to TB control in South Africa (SA). Strategies to mitigate risk and impact are explored, together with opportunities to leverage synergies from both diseases to the benefit of the National TB Programme (NTP). With the emergence of COVID-19, activities to address this new pandemic have been prioritised across all sectors. Within the health system, the health workforce and resources have been redirected away from routine services towards the new disease priority. The social determinants of health have deteriorated during the lockdown, potentially increasing progression to TB disease and impacting negatively on people with TB and their households, resulting in additional barriers to accessing TB care, with early reports of a decline in TB testing rates. Fewer TB diagnoses, less attention to adherence and support during TB treatment, poorer treatment outcomes and consequent increased transmission will increase the TB burden and TB-related mortality. People with TB or a history of TB are likely to be vulnerable to COVID-19. Modifications to current treatment practices are suggested to reduce visits to health facilities and minimise the risks of COVID-19 exposure. The COVID-19 pandemic has the potential to negatively impact on TB control in TB-endemic settings such as SA. However, there are COVID-19-related health systems-strengthening developments that may help the NTP mitigate the impact of the pandemic on TB control. By integrating TB case finding into the advanced screening, testing, tracing and monitoring systems established for COVID-19, TB case finding and linkage to care could increase, with many more TB patients starting treatment. Similarly, integrating knowledge and awareness of TB into the increased healthcare worker and community education on infectious respiratory diseases, behavioural practices around infection prevention and control, and cough etiquette, including destigmatisation of mask use, may contribute to reducing TB transmission. However, these potential gains could be overwhelmed by the impact of increasing poverty and other social determinants of health on the burden of TB.

The effect of Bacillus Calmette-Guérin (BCG) vaccination in preventing severe infectious respiratory diseases other than TB: Implications for the COVID-19 pandemic.

The rapid spread of the Coronavirus pandemic and its significant health and social impact urges the search for effective and readily available solutions to mitigate the damages. Thus, evaluating the effectiveness of existing vaccines like Bacillus Calmette-Guérin (BCG) has attracted attention. The aim of this review was evidence synthesis on the effect of BCG vaccine in preventing severe infectious respiratory disease including COVD-19, but not tuberculosis. We considered studies conducted on human participants of any study design from any country setting that were published in Enlgish. We did a systematic literature search in MEDLINE, Scopus and Google scholar databases and a free search on Google. The identified studies were appraised and relevant data were extracted using Joanna Briggs Institute tools. The extracted findings were synthesized with tables and narrative summary. Nine studies met the inclusion criteria. The findings indicated that BCG vaccine has a strong protective effect against both upper and lower acute respiratory tract infections. For instance in countries with universal BCG vaccination policy, the incidence of COVID-19 was lower compared to the counterparts. Addtionally, BCG vaccine was found to protect against infections like lethal influenza A virus, pandemic influenza (H1N1), and other acute respiratory tract infections. BCG improved the human body's immune response involving antigen-specific T cells and memory cells. It also induced adaptive functional reprogramming of mononuclear phagocytes that induce protective effects against different respiratory infections other than tuberculosis. In countries with universal BCG vaccination, the incidence and death from acute respiratory viral infection including COVID - 19 is significantly low. However, there is an urgent need for further evidence from well-designed studies to understand the possible role of BCG vaccination over time and across age groups, its possible benefits in special populations such as health workers and cost-savings related to a policy of universal BCG vaccination.

Impact of COVID-19 pandemic response on uptake of routine immunizations in Sindh, Pakistan: An analysis of provincial electronic immunization registry data.

BACKGROUND: COVID-19 pandemic has affected routine immunization globally. Impact will likely be higher in low and middle-income countries with limited healthcare resources and fragile health systems. We quantified the impact, spatial heterogeneity, and determinants for childhood immunizations of 48 million population affected in the Sindh province of Pakistan. METHODS: We extracted individual immunization records from real-time provincial Electronic Immunization Registry from September 23, 2019, to July 11, 2020. Comparing baseline (6 months preceding the lockdown) and the COVID-19 lockdown period, we analyzed the impact on daily immunization coverage rate for each antigen by geographical area. We used multivariable logistic regression to explore the predictors associated with immunizations during the lockdown. RESULTS: There was a 52.5% decline in the daily average total number of vaccinations administered during lockdown compared to baseline. The highest decline was seen for Bacille Cal-mette Guérin (BCG) (40.6% (958/2360) immunization at fixed sites. Around 8438 children/day were missing immunization during the lockdown. Enrollments declined furthest in rural districts, urban sub-districts with large slums, and polio-endemic super high-risk sub-districts. Pentavalent-3 (penta-3) immunization rates were higher in infants born in hospitals (RR: 1.09; 95% CI: 1.04-1.15) and those with mothers having higher education (RR: 1.19-1.50; 95% CI: 1.13-1.65). Likelihood of penta-3 immunization was reduced by 5% for each week of delayed enrollment into the immunization program. CONCLUSION: One out of every two children in Sindh province has missed their routine vaccinations during the provincial COVID-19 lockdown. The pool of un-immunized children is expanding during lockdown, leaving them susceptible to vaccine-preventable diseases. There is a need for tailored interventions to promote immunization visits and safe service delivery. Higher maternal education, facility-based births, and early enrollment into the immunization program continue to show a positive association with immunization uptake, even during a challenging lockdown.

Severe acute respiratory syndrome coronavirus-2 and pulmonary tuberculosis: convergence can be fatal.

Disease associated with SARS-CoV-2 also termed as Coronavirus disease 2019 or COVID-19, has become a potential threat to public health by spreading across more than 200 countries worldwide within a short span of time. Tuberculosis (TB) is already existing as unprecedented pandemic worldwide over several years. Both diseases have many overlapping features but there are striking differences too. There is usually chronicity of symptoms in TB as compared to acute or rapid progression in COVID-19. Little evidence exists regarding TB and COVID-19 coinfection. It is anticipated that person with TB either in active, previously treated or latent forms are more at risk of poor outcomes with COVID-19. The relationship between the two diseases is still unclear at present, and more studies are needed to enable analyses of interactions and determinants of outcomes in patients affected by both the diseases. Most of the countries across the world imposed nationwide lockdown to promote social distancing, which is one important preventive measure to mitigate the spread of COVID-19 pandemic. However, it becomes quite challenging to ensure smooth functioning of programmatic services, leading to disruption of routine TB care, leading to transmission of infection. Health authorities should frame polices that can support TB patients by providing diagnostic, management and prevention services without any interruption during this era of ongoing COVID-19 pandemic. Effort should be made to control both the diseases simultaneously and avoid unfavourable outcome in near future.

Assessment of adequacy of respiratory infection prevention in hospitals of Inner Mongolia, China: a cross-sectional study using unannounced standardized patients.

INTRODUCTION: Recent respiratory infectious disease (RID) outbreaks of influenza and the novel coronavirus have resulted in global pandemics. RIDs can trigger nosocomial infections if not adequately prevented. OBJECTIVE: The objective of this study was to rate the adequacy of healthcare workers (HCWs) and hospital settings on RID prevention using unannounced standardized patients (USP) in clinical settings of hospital gateways. METHODS: Trained USPs visited 5 clinical settings: information desks, registration desks, two outpatient departments and the emergency departments in 10 hospitals across 3 cities of Inner Mongolia, China. USPs observed the hospital air ventilation and distance from the nearest hand-washing facilities to each clinical setting, then mimicked symptoms of either tuberculosis or influenza before observing the HCW's behavior. A total of 480 clinical-setting assessments were made by 19 USPs. RESULTS: The overall adequacy of triage services was 86.7% and for prevention of the spread of airborne droplets was 83.5%. Almost all hospitals offered adequate air ventilation. Compared to the information desk, adequacy of triage and preventing the spread of airborne droplets by physicians in the three clinical departments was less likely to be adequate. Triage services for USPs simulating symptoms of influenza were 2.6 times more likely to be adequate than for those simulating symptoms of tuberculosis but there was no significant difference in the prevention of the spread of airborne droplets. CONCLUSIONS: There is a need to improve respiratory infectious disease procedures in our study hospitals, especially in outpatient and emergency departments.

COVID-19: Avoiding a second tragedy in a tuberculosis burdened country.

To the Editor Novel Coronavirus disease (COVID-19) was first notified in December 2019 from Wuhan, China. Now, it has spread rapidly and has been declared a pandemic affecting over 200 countries with widespread morbidity and mortality. It has been postulated that the most vulnerable population are the elderly, people living in crowded areas, children and immune-compromised individuals, such as people living with human immunodeficiency virus (HIV). The correlation of tuberculosis (TB), HIV and malnutrition are well documented and hence, people with tuberculosis should be considered as special population in this pandemic. TB is an ancient disease among humans recorded as far back as seventy thousand years which was declared a global public health emergency in 1993 by the World Health Organisation (WHO). India has the highest TB burden in the world.