The Covid-19 and TB Syndemic: Differences and Similarities

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Background

For centuries, tuberculosis (TB) has been the deadliest infectious disease globally. Its infamous position was replaced only recently by Covid-19. Over the last 200 years, an estimated 1 billion people have died of TB, on average an estimated 5 million annually. In the last two years, Covid-19 has killed more than 6 million, which according to WHO estimates could be two- to threefold higher. Covid-19 is caused by the Corona virus SARS-CoV-2, whilst Mycobacterium tuberculosis (Mtb) is the etiologic agent of TB. Hence, they are very different pathogens, which both primarily affect the lung and are transmitted through the aerogenic route with aerosols playing a major role. TB is a chronic disease which largely involves immunopathologic mechanisms. Although Covid-19 is an acute disease in most cases, in some patients a chronic stage develops, termed Long Covid, which is characterized by immunopathology.

SARS-CoV-2 expresses the Spike protein which allows it to bind to the angiotensin-converting enzyme receptor 2 (ACE2) for entry into host cells, notably, but not exclusively, epithelial cells. Mtb is primarily engulfed by mononuclear phagocytes which serve as major players in defense against and as habitat for this pathogen. This leads to the formation of granulomas, where Mtb is contained. Although containment may last lifelong, disease will only develop in an about 10% of infected individuals. Containment of Mtb prevents transmission and only once disease has developed, patients become contagious. Hence, transmission of Mtb depends on prior host cell damage/symptoms, whereas transmission of SARS-CoV-2 apparently is independent from pathology/symptoms. Similarly, SARS-CoV-2 causes disease in only a proportion of infected individuals. However, in contrast to TB, healthy individuals infected with SARS-CoV-2 are contagious. Thus, transmission of SARS-CoV-2 apparently is independent from pathology/symptoms.

A threatening issue in the Covid-19 field is the rapid emergence of variants that, at least partly, evade protective immunity, caused by infection or by vaccination. Evolution of Mtb variants occurs as well. This mostly leads to drug resistance, but mechanisms to evade immune responses have been described, notably in relation to susceptibility and immunopathology.

Protective antigens have been defined in the case of for SARS-CoV-2, but are missing in TB. Hence, correlates of protection can be easily defined for Covid-19. Accordingly, neutralizing antibodies play a major role in Covid-19. Yet, non-neutralizing antibodies have been found to play a critical role in immunity against TB. Central to protective immunity against TB is the balanced interplay between different T cell subsets and it is most likely that T cells also play a role in prevention of disease caused by SARS-CoV-2. Accordingly, vaccines against Covid-19 focus on neutralizing antibodies, whereas vaccines against TB emphasize activation of the right combination of different T cell populations. Differences in immunity, at least in part, are a major reason for rapid vaccine development against Covid-19 within one year. A vaccine against TB has been developed more than 100 years ago, named Bacille-Calmette-Guérin (BCG). However, this vaccine is insufficient since it only protects infants against TB. Novel vaccines against TB are urgently needed and over the last decades several candidates have entered the clinical trial pipeline.
BCG has been proven to show heterologous protection against unrelated viral pathogens and currently clinical trials are underway to test whether this holds true for SARS-CoV-2, as well. Successful vaccines against Covid-19 include primary mRNA vaccines and also adenovirus vaccines. Moreover, inactivated viral vaccines in adjuvant are being used. Vaccine candidates against TB which have entered clinical trials include subunit vaccines (adjuvanted
mycobacterial protein antigens and viral vectors expression mycobacterial antigens) and whole cell vaccines (killed mycobacteria and attenuated Mtb or improved recombinant BCG). Lessons from vaccine development in the field of TB and Covid-19 therefore will provide mutual benefit for future developments.

This research topic discusses different aspects related to the host immune response against two major infectious diseases, Covid-19 and TB. Strong emphasis will be given to comparative views of these two diseases which share some similarities, but are also distinct from each other. The research topic starts with a general overview on the global impact of the two diseases as well as a brief description of recent accomplishments in our understanding of the mechanisms underlying protection and pathology and in vaccine research and development. This is followed by a general perspective on newly emerging and re-emerging infectious diseases. Thereafter, comprehensive review(s) on clinical features of the two diseases will be provided. Subsequently, the impact of the emergence of new variants will be discussed which is of particular importance for Covid-19. Then the role of genetic features involved in reemergence of TB immune evasion of Mtb will be discussed.

The major part of this research topic is aimed at better understanding of the immune response. It will cover the major components of immunity that are relevant to protection against Covid-19 and TB. In the case of Covid-19, neutralizing antibodies as central mediators of protection will be given adequate space. In addition, the role of non-neutralizing antibodies and of T lymphocytes will be considered. In TB, different T cell subsets represent a major component of protective immunity and hence their interplay will be discussed extensively. However, antibodies, probably mostly non-neutralizing antibodies, will be considered, as well. In both diseases, the immune response also plays a significant role in pathogenesis and several aspects will be reviewed focusing both on shared and unique mechanisms. Having discussed the various aspects of immunity in protection and pathology, this research topic turns to vaccine research and development which has been without precedent for Covid-19 and is much slower for TB. Central to this success is the Spike protein which as protective antigen is critical for vaccines against Covid-19. Aside from neutralizing antibodies against Spike, the role of non-neutralizing antibodies and T cells for vaccine efficacy against Covid-19 will be discussed, as well. The complexity of vaccine development against TB which lags behind the success story of vaccines against Covid-19 will be taken up next. The only available vaccine against TB, Bacille-Calmette-Guérin (BCG), confers partial protection but is insufficient for protection against the most prevalent form, pulmonary TB. On the other hand, BCG stimulates heterologous protection against pulmonary viral infections including Covid-19 and this issue will be included in the discussion on vaccines against the two diseases. The most broadly deployed vaccines against Covid-19 are based on a new technology, namely mRNA. This novel type of vaccines will not only be considered for Covid-19 but also its potential for future TB vaccination strategies will be discussed. Adenoviruses have been successful as vaccine vectors for Covid-19 and are also being considered for TB in clinical trials. Hence, this vaccine type will also be reviewed. Lessons learned from clinical trials with vaccines against Covid-19 and TB will be taken up and followed by the role of low-cost vaccine production and deployment in low-income countries. After all, vaccines against Covid-19 benefitted from more or less unlimited financial support. In contrast, TB vaccine development faces insufficient financial support.

Overall, this research topic will not only summarize most recent advances in our understanding of host protection and pathology in Covid-19 and TB, it will also provide a forum for discussion on where to go in the future, both in more basic science of immunology and the more applied research of vaccinology.

The research topic will be mostly comprise review articles although in certain cases original papers will be included.

Prof. Kaufmann is a co-holder of a patent for the tuberculosis vaccine, VPM1002, which has been licensed to Vakzine Projekt Management GmbH, Hannover, Germany and Serum Institute of India PVT. Ltd., Pune, India. The other Topic Editors declare no competing interests with regard to the Research Topic subject.

Keywords: Covid-19, tuberculosis, SARS-CoV-2, Mycobacterium tuberculosis, immunogenetics, mutations and variants, immune protection, immunopathology, immune evasion, T lymphocytes, neutralizing antibodies, non-neutralizing antibodies, clinical vaccine trials, mRNA

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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