A guide to immunotherapy for COVID-19 van de Veerdonk, Frank L; Giamarellos-Bourboulis, Evangelos; Pickkers, Peter ...
Nature medicine,
01/2022, Volume:
28, Issue:
1
Journal Article
Peer reviewed
Open access
Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some ...remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trials of host-directed therapy. We discuss patient stratification and propose an algorithm to guide the use of immunotherapy strategies in the clinic. This will not only help guide treatment decisions, but may also help to design future trials that investigate immunotherapy in other severe infections.
Review of how vaccines have long‐lasting effects on the innate immune system.
An increasing body of evidence shows that the innate immune system has adaptive characteristics that involve a ...heterologous memory of past insults. Both experimental models and proof‐of‐principle clinical trials show that innate immune cells, such as monocytes, macrophages, and NK cells, can provide protection against certain infections in vaccination models independently of lymphocytes. This process is regulated through epigenetic reprogramming of innate immune cells and has been termed “trained immunity.” It has been hypothesized that induction of trained immunity is responsible for the protective, nonspecific effects induced by vaccines, such as BCG, measles vaccination, and other whole‐microorganism vaccines. In this review, we will present the mechanisms of trained immunity responsible for the long‐lasting effects of vaccines on the innate immune system.
Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed 'trained ...immunity'. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the induction of immunity and protective efficacy of the anti-tuberculosis BCG vaccine against a controlled human malaria infection. After malaria challenge infection, BCG vaccinated volunteers present with earlier and more severe clinical adverse events, and have significantly earlier expression of NK cell activation markers and a trend towards earlier phenotypic monocyte activation. Furthermore, parasitemia in BCG vaccinated volunteers is inversely correlated with increased phenotypic NK cell and monocyte activation. The combined data demonstrate that BCG vaccination alters the clinical and immunological response to malaria, and form an impetus to further explore its potential in strategies for clinical malaria vaccine development.
Summary
The tuberculosis (TB) vaccine Bacillus Calmette‐Guérin (BCG) was introduced 100 years ago, but as it provides insufficient protection against TB disease, especially in adults, new vaccines ...are being developed and evaluated. The discovery that BCG protects humans from becoming infected with Mycobacterium tuberculosis (Mtb) and not just from progressing to TB disease provides justification for considering Mtb infection as an endpoint in vaccine trials. Such trials would require fewer participants than those with disease as an endpoint. In this review, we first define Mtb infection and disease phenotypes that can be used for mechanistic studies and/or endpoints for vaccine trials. Secondly, we review the evidence for BCG‐induced protection against Mtb infection from observational and BCG re‐vaccination studies, and discuss limitations and variation of this protection. Thirdly, we review possible underlying mechanisms for BCG efficacy against Mtb infection, including alternative T cell responses, antibody‐mediated protection, and innate immune mechanisms, with a specific focus on BCG‐induced trained immunity, which involves epigenetic and metabolic reprogramming of innate immune cells. Finally, we discuss the implications for further studies of BCG efficacy against Mtb infection, including for mechanistic research, and their relevance to the design and evaluation of new TB vaccines.
Non-specific protective effects of certain vaccines have been reported, and long-term boosting of innate immunity, termed trained immunity, has been proposed as one of the mechanisms mediating these ...effects. Several epidemiological studies suggested cross-protection between influenza vaccination and COVID-19. In a large academic Dutch hospital, we found that SARS-CoV-2 infection was less common among employees who had received a previous influenza vaccination: relative risk reductions of 37% and 49% were observed following influenza vaccination during the first and second COVID-19 waves, respectively. The quadrivalent inactivated influenza vaccine induced a trained immunity program that boosted innate immune responses against various viral stimuli and fine-tuned the anti-SARS-CoV-2 response, which may result in better protection against COVID-19. Influenza vaccination led to transcriptional reprogramming of monocytes and reduced systemic inflammation. These epidemiological and immunological data argue for potential benefits of influenza vaccination against COVID-19, and future randomized trials are warranted to test this possibility.
Summary Background Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens ...containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. Methods In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT01158755. Findings 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC0–6 ; 78·7 mg.h/L 95% CI 71·0–87·3 vs 26·0 mg.h/L 19·0–35·6), maximum plasma concentrations (Cmax ; 22·1 mg/L 19·9–24·6 vs 6·3 mg/L 4·9–8·3), and concentrations in cerebrospinal fluid (0·60 mg/L 0·46–0·78 vs 0·21 mg/L 0·16–0·27). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC0–6 (31·5 mg.h/L 24·1–41·1 vs 15·1 mg.h/L 12·8–17·7), Cmax (7·4 mg/L 5·6–9·6 vs 3·9 mg/L 3·2–4·8), and drug concentrations in the cerebrospinal fluid (2·43 mg/L 1·81–3·27 vs 1·52 mg/L 1·28–1·82). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten 35% vs 20 65%), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20–0·91; p=0·03). Interpretation These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. Funding Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.
Abstract
Background
Metformin, the most widely administered diabetes drug, has been proposed as a candidate adjunctive host-directed therapy for tuberculosis, but little is known about its effects on ...human host responses to Mycobacterium tuberculosis.
Methods
We investigated in vitro and in vivo effects of metformin in humans.
Results
Metformin added to peripheral blood mononuclear cells from healthy volunteers enhanced in vitro cellular metabolism while inhibiting the mammalian target of rapamycin targets p70S6K and 4EBP1, with decreased cytokine production and cellular proliferation and increased phagocytosis activity. Metformin administered to healthy human volunteers led to significant downregulation of genes involved in oxidative phosphorylation, mammalian target of rapamycin signaling, and type I interferon response pathways, particularly following stimulation with M. tuberculosis, and upregulation of genes involved in phagocytosis and reactive oxygen species production was increased. These in vivo effects were accompanied by a metformin-induced shift in myeloid cells from classical to nonclassical monocytes. At a functional level, metformin lowered ex vivo production of tumor necrosis factor α, interferon γ, and interleukin 1β but increased phagocytosis activity and reactive oxygen species production.
Conclusion
Metformin has a range of potentially beneficial effects on cellular metabolism, immune function, and gene transcription involved in innate host responses to M. tuberculosis.
Metformin has shown beneficial effects in a murine model of tuberculosis. Using in-vitro and in-vivo studies we show that metformin has beneficial effects on cellular metabolism, immune function and genetranscription involved in innate host responses to M. tuberculosis in humans.
Diabetes Mellitus increases the risk of developing Tuberculosis (TB) disease by about three times; it also doubles the risk of death during TB treatment and other poor TB treatment outcomes. Diabetes ...may increase the risk of latent infection with
(LTBI), but the magnitude of this effect is less clear. Whilst this syndemic has received considerable attention, most of the published research has focussed on screening for undiagnosed diabetes in TB patients or observational follow-up of TB treatment outcomes by diabetes status. There are thus substantial research and policy gaps, particularly with regard to prevention of TB disease in people with diabetes and management of patients with TB-diabetes, both during TB treatment and after successful completion of TB treatment, when they likely remain at high risk of TB recurrence, mortality from TB and cardiovascular disease. Potential strategies to prevent development of TB disease might include targeted vaccination programmes, screening for LTBI and preventive therapy among diabetes patients or, perhaps ideally, improved diabetes management and prevention. The cost-effectiveness of each of these, and in particular how each strategy might compare with targeted TB prevention among other population groups at higher risk of developing TB disease, is also unknown. Despite research gaps, clinicians urgently need practical management advice and more research evidence on the choice and dose of different anti-diabetes medication and effective medical therapies to reduce cardiovascular risks (statins, anti-hypertensives and aspirin). Substantial health system strengthening and integration may be needed to prevent these at risk patients being lost to care at the end of TB treatment.
Innate immune memory, or trained immunity, has recently been described to be an important property of cells of the innate immune system. Due to the increased interest in this important new field of ...immunological investigation, we sought to determine the optimal conditions for an in vitro experimental protocol of monocyte training using three of the most commonly used training stimuli from the literature: β-glucan, the bacillus Calmette-Guérin (BCG) vaccine, and oxidized low-density lipoprotein (oxLDL). We investigated and optimized a protocol of monocyte trained immunity induced by an initial training period with β-glucan, BCG, or oxLDL, followed by washing and resting of the cells and, thereafter, restimulation with secondary bacterial stimuli. The training and resting time intervals were varied to identify the optimal setting for the long-term induction of trained immunity. Trained immunity was assessed in terms of the secondary cytokine response, the production of reactive oxygen species, cell morphology, and induction of glycolysis. Monocytes primed with β-glucan, BCG, and oxLDL showed increased pro- and anti-inflammatory cytokine responses upon restimulation with nonrelated stimuli. Also, all three stimuli induced a switch to glycolysis (the Warburg effect). These effects were most pronounced when the training interval was 24 h and the resting time interval was 6 days. Training with BCG and oxLDL also led to the increased production of reactive oxygen species, whereas training with β-glucan led to the decreased production of reactive oxygen species. We describe the optimal conditions for an in vitro experimental model with human primary monocytes for study of the induction of trained innate immunity by microbial and metabolic stimuli.
Resolving trained immunity with systems biology Koeken, Valerie A.C.M.; Crevel, Reinout; Netea, Mihai G. ...
European journal of immunology,
April 2021, 2021-Apr, 2021-04-00, 20210401, Volume:
51, Issue:
4
Journal Article
Peer reviewed
Open access
Trained immunity is characterized by long‐term functional reprogramming of innate immune cells following challenge with pathogens or microbial ligands during infection or vaccination. This cellular ...reprogramming leads to increased responsiveness upon restimulation, and is mediated through epigenetic and metabolic modifications. In this review, we describe how molecular mechanisms underlying trained immunity, for example, induced by β‐glucan or Bacille Calmette‐Guérin (BCG) vaccination, can be investigated by using and integrating different layers of information including genome, epigenome, transcriptome, proteome, metabolome, microbiome, immune cell phenotyping, and function. We also describe the most commonly used experimental and computational techniques. Finally, we provide a number of examples of how a systems biology approach was applied to study trained immunity to understand interindividual variation or the complex interplay between molecular layers. In conclusion, trained immunity represents an opportunity for regulating innate immune function, and understanding the complex interplay of mechanisms that mediate trained immunity might enable us to employ it as a clinical tool in the future.
Trained immunity is the functional adaptation of innate immune cells to a more responsive state. The underlying mechanisms and interindividual variation could be studied using a multiomics approach, integrating, for example, genome, transcriptome, and proteome data. These insights could ultimately enable us to employ trained immunity as a clinical tool.
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