A mathematical model of SARS-CoV-2 immunity predicts paxlovid rebound.

Nirmatrelvir/ritonavir (Paxlovid), an oral antiviral medication targeting SARS-CoV-2, remains an important treatment for COVID-19. Initial studies of nirmatrelvir/ritonavir were performed in SARS-CoV-2 unvaccinated patients without prior confirmed SARS-CoV-2 infection; however, most individuals have now either been vaccinated and/or have experienced SARS-CoV-2 infection. After nirmatrelvir/ritonavir became widely available, reports surfaced of "Paxlovid rebound," a phenomenon in which symptoms (and SARS-CoV-2 test positivity) would initially resolve, but after finishing treatment, symptoms and test positivity would return. We used a previously described parsimonious mathematical model of immunity to SARS-CoV-2 infection to model the effect of nirmatrelvir/ritonavir treatment in unvaccinated and vaccinated patients. Model simulations show that viral rebound after treatment occurs only in vaccinated patients, while unvaccinated (SARS-COV-2 naïve) patients treated with nirmatrelvir/ritonavir do not experience any rebound in viral load. This work suggests that an approach combining parsimonious models of the immune system could be used to gain important insights in the context of emerging pathogens.

A Third Dose of SARS-CoV-2 mRNA Vaccine Improves Immune Response in Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) patients have an increased risk of morbidity and mortality following SARS-CoV-2 infection. Vaccination in these patients is prioritized, and monitoring of the immune response is paramount to define further vaccination strategies. This prospective study included a cohort of 100 adult CKD patients: 48 with kidney transplant (KT) and 52 on hemodialysis without prior COVID-19. The patients were assessed for humoral and cellular immune responses after four months of an anti-SARS-CoV-2 primary two-dose vaccination scheme (CoronaVac or BNT162b2) and one month after a booster third dose of BNT162b2 vaccine. We identified poor cellular and humoral immune responses in the CKD patients after a primary vaccination scheme, and these responses were improved by a booster. Robust polyfunctional CD4+ T cell responses were observed in the KT patients after a booster, and this could be attributed to a higher proportion of the patients having been vaccinated with homologous BNT162b2 schemes. However, even after the booster, the KT patients exhibited lower neutralizing antibodies, attributable to specific immunosuppressive treatments. Four patients suffered severe COVID-19 despite three-dose vaccination, and all had low polyfunctional T-cell responses, underscoring the importance of this functional subset in viral protection. In conclusion, a booster dose of SARS-CoV-2 mRNA vaccine in CKD patients improves the impaired humoral and cellular immune responses observed after a primary vaccination scheme.

Histone mRNA polyadenylation-mediated inflammation underlies various virus infections and cancers.

The mechanistic understanding of virus infection and inflammation in many diseases is incomplete. Normally, messenger RNA (mRNA) tails of replication-dependent histones (RDH) that safeguard naked nuclear DNAs are protected by a specialized stem-loop instead of polyadenylation. Here, we showed that infection by various RNA viruses (including severe acute respiratory syndrome coronavirus 2) induced aberrant polyadenylation of RDH mRNAs (pARDH) that resulted in inflammation or cellular senescence, based on which we constructed a pARDH inflammation score (pARIS). We further investigated pARIS elevation in various disease conditions, including different types of virus infection, cancer, and cellular senescence. Notably, we found that pARIS was positively correlated with coronavirus disease 2019 severity in specific immune cell types. We also detected a subset of HIV-1 elite controllers characterized by pARDH "flipping" potentially mediated by HuR. Importantly, pARIS was positively associated with transcription of endogenous retrovirus but negatively associated with most immune cell infiltration in tumors of various cancer types. Finally, we identified and experimentally verified two pARIS regulators, ADAR1 and ZKSCAN1, which was first linked to inflammation. The ZKSCAN1 was known as a transcription factor but instead was shown to regulate pARIS as a novel RNA binding protein. Both regulators were upregulated under most infection and inflammation conditions. In conclusion, we unraveled a potential antiviral mechanism underlying various types of virus infections and cancers.

The role of interleukin-21 in COVID-19 vaccine-induced B cell-mediated immune responses in patients with kidney disease and kidney transplant recipients.

T-cell-mediated help to B cells is required for the development of humoral responses, in which the cytokine interleukin (IL)-21 is key. Here, we studied the mRNA-1273 vaccine-induced SARS-CoV-2-specific memory T-cell IL-21 response, memory B cell response, and immunoglobulin (Ig)G antibody levels in peripheral blood at 28 days after the second vaccination by ELISpot and the fluorescent bead-based multiplex immunoassay, respectively. We included 40 patients with chronic kidney disease (CKD), 34 patients on dialysis, 63 kidney transplant recipients (KTR), and 47 controls. We found that KTR, but not patients with CKD and those receiving dialysis, showed a significantly lower number of SARS-CoV-2-specific IL-21 producing T cells than controls (P < .001). KTR and patients with CKD showed lower numbers of SARS-CoV-2-specific IgG-producing memory B cells when compared with controls (P < .001 and P = .01, respectively). The T-cell IL-21 response was positively associated with the SARS-CoV-2-specific B cell response and the SARS-CoV-2 spike S1-specific IgG antibody levels (both Pearson r = 0.5; P < .001). In addition, SARS-CoV-2-specific B cell responses were shown to be IL-21 dependent. Taken together, we show that IL-21 signaling is important in eliciting robust B cell-mediated immune responses in patients with kidney disease and KTR.

Host Defenses to Viruses

Virus infections continue to pose a substantial threat to human health. A prime example is the ongoing 2019 coronavirus pandemic caused by the novel virus SARS-CoV-2. Unraveling the intricacies of immune defenses against viruses should lead to improved control of infections through the design of new vaccines and therapies. Our understanding of the fundamental cellular and molecular mechanisms involved in the immune system's response to virus infection has improved substantially in recent years. This wealth of new information and the promise of new insight from systems biology approaches continue to drive research in this field. Such knowledge has revealed why viruses sometimes induce immune dysfunction or trigger disastrous pathology and has paved the way for new therapies being tested against chronic and emerging infections. In this chapter, we briefly summarize the general concepts in immunity to virus infections and highlight some of the key challenges remaining for the future. Virus infections continue to pose a substantial threat to human health, and many cannot be controlled effectively with current vaccines or antiviral approaches. © 2023 Elsevier Ltd. All rights reserved.

Antigen epitopes of animal coronaviruses: a mini-review.

Coronaviruses are widespread in nature and can infect mammals and poultry, making them a public health concern. Globally, prevention and control of emerging and re-emerging animal coronaviruses is a great challenge. The mechanisms of virus-mediated immune responses have important implications for research on virus prevention and control. The antigenic epitope is a chemical group capable of stimulating the production of antibodies or sensitized lymphocytes, playing an important role in antiviral immune responses. Thus, it can shed light on the development of diagnostic methods and novel vaccines. Here, we have reviewed advances in animal coronavirus antigenic epitope research, aiming to provide a reference for the prevention and control of animal and human coronaviruses. Supplementary Information: The online version contains supplementary material available at 10.1186/s44149-023-00080-0.

Innate and adaptive immune response in SARS-CoV-2 infection-Current perspectives.

Coronavirus disease 2019 (COVID-19) has been a global pandemic, caused by a novel coronavirus strain with strong infectivity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With the in-depth research, the close relationship between COVID-19 and immune system has been dug out. During the infection, macrophages, dendritic cells, natural killer cells, CD8+ T cells, Th1, Th17, Tfh cells and effector B cells are all involved in the anti-SARS-CoV-2 responses, however, the dysfunctional immune responses will ultimately lead to the excessive inflammation, acute lung injury, even other organ failure. Thus, a detailed understanding of pertinent immune response during COVID-19 will provide insights in predicting disease outcomes and developing appropriate therapeutic approaches. In this review, we mainly clarify the role of immune cells in COVID-19 and the target-vaccine development and treatment.

Immunogenicity and reactogenicity of mRNA COVID-19 vaccine booster administered by intradermal or intramuscular route in Thai Older adults.

INTRODUCTION: Intradermal (ID) vaccination may alleviate COVID-19 vaccine shortages and vaccine hesitancy. METHODS: Persons aged ≥65 years who were vaccinated with 2-dose ChAdOx1 12-24 weeks earlier were randomized to receive a booster vaccination by either ID (20-mcg mRNA1273 or 10-mcg BNT162b2) or intramuscular (IM) (100-mcg mRNA1273 or 30-mcg BNT162b2) route. Anti-receptor binding domain (anti-RBD) IgG, neutralizing antibody (NAb), and IFNγ-producing cells were measured at 2-4 weeks following vaccination. RESULTS: Of 210 participants enrolled, 70.5% were female and median age was 77.5 years (interquartile range: 71-84). Following booster dose, both ID vaccination induced 37% lower levels of anti-RBD IgG than IM vaccination of the same vaccine. NAb titers against ancestral and omicron BA.1 was highest following IM mRNA-1273 (geometric mean 1,718 and 617), followed by ID mRNA-1273 (1,212 and 318), IM BNT162b2 (713 and 230), and ID BNT162b2 (587 and 148), respectively. Spike-specific IFNγ responses were similar or higher in the ID groups when compared with IM groups. ID route tended to have lower systemic AEs, although more local AEs reported in ID mRNA-1273 group. CONCLUSIONS: Fractional ID vaccination induced lower humoral but comparable cellular immunity compared to IM and may be an alternative option for older people.

The IFN-stimulated gene IFI27 counteracts innate immune responses after viral infections by interfering with RIG-I signaling.

The recognition of viral nucleic acids by host pattern recognition receptors (PRRs) is critical for initiating innate immune responses against viral infections. These innate immune responses are mediated by the induction of interferons (IFNs), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines. However, regulatory mechanisms are critical to avoid excessive or long-lasting innate immune responses that may cause detrimental hyperinflammation. Here, we identified a novel regulatory function of the ISG, IFN alpha inducible protein 27 (IFI27) in counteracting the innate immune responses triggered by cytoplasmic RNA recognition and binding. Our model systems included three unrelated viral infections caused by Influenza A virus (IAV), Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), and Sendai virus (SeV), and transfection with an analog of double-stranded (ds) RNA. Furthermore, we found that IFI27 has a positive effect on IAV and SARS-CoV-2 replication, most likely due to its ability to counteract host-induced antiviral responses, including in vivo. We also show that IFI27 interacts with nucleic acids and PRR retinoic acid-inducible gene I (RIG-I), being the interaction of IFI27 with RIG-I most likely mediated through RNA binding. Interestingly, our results indicate that interaction of IFI27 with RIG-I impairs RIG-I activation, providing a molecular mechanism for the effect of IFI27 on modulating innate immune responses. Our study identifies a molecular mechanism that may explain the effect of IFI27 in counterbalancing innate immune responses to RNA viral infections and preventing excessive innate immune responses. Therefore, this study will have important implications in drug design to control viral infections and viral-induced pathology.

Robust Vaccine-Induced as Well as Hybrid B- and T-Cell Immunity across SARS-CoV-2 Vaccine Platforms in People with HIV.

Few studies have comprehensively compared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced and hybrid B- and T-cell responses in people with HIV (PWH) to those in comparable controls without HIV. We included 195 PWH and 246 comparable controls from the AGEhIV COVID-19 substudy. A positive nucleocapsid antibody (INgezim IgA/IgM/IgG) or self-reported PCR test defined prior SARS-CoV-2 infection. SARS-CoV-2 anti-spike (anti-S) IgG titers and anti-S IgG production by memory B cells were assessed. Neutralizing antibody titers were determined in a subset of participants. T-cell responses were assessed by gamma interferon (IFN-γ) release and activation-induced marker assay. We estimated mean differences in postvaccination immune responses (ß) between levels of determinants. Anti-S IgG titers and anti-S IgG production by memory B cells were not different between PWH and controls. Prior SARS-CoV-2 infection (ß = 0.77), receiving mRNA vaccine (ß = 0.56), female sex (ß = 0.24), fewer days between last vaccination and sampling (ß = 0.07), and a CD4/CD8 ratio of <1.0 (ß = -0.39) were independently associated with anti-S IgG titers, but HIV status was not. Neutralization titers against the ancestral and Delta and Omicron SARS-CoV-2 variants were not different between PWH and controls. IFN-γ release was higher in PWH. Prior SARS-CoV-2 infection (ß = 2.39), HIV-positive status (ß = 1.61), and fewer days between last vaccination and sampling (ß = 0.23) were independently associated with higher IFN-γ release. The percentages of SARS-CoV-2-reactive CD4+ and CD8+ T cells, however, were not different between PWH and controls. Individuals with well-controlled HIV generally mount robust vaccine-induced as well as hybrid B- and T-cell immunity across SARS-CoV-2 vaccine platforms similar to controls. Determinants of a reduced vaccine response were likewise largely similar in both groups and included a lower CD4/CD8 ratio. IMPORTANCE Some studies have suggested that people with HIV may respond less well to vaccines against SARS-CoV-2. We comprehensively compared B- and T-cell responses to different COVID-19 vaccines in middle-aged persons with well-treated HIV and individuals of the same age without HIV, who were also highly comparable in terms of demographics and lifestyle, including those with prior SARS-CoV-2 infection. Individuals with HIV generally mounted equally robust immunity to the different vaccines. Even stronger immunity was observed in both groups after prior SARS-CoV-2 infection. These findings are reassuring with respect to the efficacy of SARS-Cov-2 vaccines for the sizable and increasing global population of people with HIV with access and a good response to HIV treatment.

Host immune responses in aged rhesus macaques against BBV152, an inactivated SARS-CoV-2 vaccine, and cross-neutralization with beta and delta variants.

The magnitude and duration of immune response to COVID-19 vaccination in older adults are known to be adversely affected due to immunosenescence and inflammaging. The threat of emerging variants warrants studies on immune response in older adults to primary vaccination and booster doses so as to understand the effectiveness of vaccines in countering the threat of emerging variants. Non-human primates (NHPs) are ideal translational models, as the immunological responses in NHPs are similar to those in humans, so it enables us to understand host immune responses to the vaccine. We initially studied humoral immune responses in aged rhesus macaques employing a three-dose regimen of BBV152, an inactivated SARS-CoV-2 vaccine. Initially, the study investigated whether the third dose enhances the neutralizing antibody (Nab) titer against the homologous virus strain (B.1) and variants of concern (Beta and Delta variants) in aged rhesus macaques immunized with BBV152, adjuvanted with Algel/Algel-IMDG (imidazoquinoline). Later, we also attempted to understand cellular immunity in terms of lymphoproliferation against γ-inactivated SARS-CoV-2 B.1 and delta in naïve and vaccinated rhesus macaques after a year of the third dose. Following the three-dose regimen with 6 µg of BBV152 with Algel-IMDG, animals had increased Nab responses across all SARS-CoV-2 variants studied, which suggested the importance of booster dose for the enhanced immune response against SARS-CoV-2-circulating variants. The study also revealed the pronounced cellular immunity against B.1 and delta variants of SARS-CoV-2 in the aged rhesus macaques even after a year of vaccination.

Adipokines, and not vitamin D, associate with antibody immune responses following dual BNT162b2 vaccination within individuals younger than 60 years.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) led to a global health outbreak known as the COVID-19 pandemic which has been lasting since March 2020. Vaccine became accessible to people only at the beginning of 2021 which greatly helped reducing the mortality rate and severity of COVID-19 infection afterwards. The efficacy of vaccines was not fully known and studies documenting the immune responses following vaccination are continuing to emerge. Recent evidence indicate that natural infection prior vaccination may improve the antibody and cellular immune responses, while little is known about the factors influencing those processes. Here we investigated the antibody responses following BNT162b2 vaccination in relation to previous-infection status and age, and searched for possible biomarkers associated with the observed changes in immune responses. We found that the previous-infection status caused at least 8-times increase in the antibody titres, effect that was weaker in people over 60 years old and unaltered by the vitamin D serum levels. Furthermore, we identified adiponectin to positively associate with antibody responses and negatively correlate with pro-inflammatory molecules (MCP-1, factor D, CRP, PAI-1), especially in previously-infected individuals.

Monoclonal antibody designed for SARS-nCoV-2 spike protein of receptor binding domain on antigenic targeted epitopes for inhibition to prevent viral entry.

SARS, or severe acute respiratory syndrome, is caused by a novel coronavirus (COVID-19). This situation has compelled many pharmaceutical R&D companies and public health research sectors to focus their efforts on developing effective therapeutics. SARS-nCoV-2 was chosen as a protein spike to targeted monoclonal antibodies and therapeutics for prevention and treatment. Deep mutational scanning created a monoclonal antibody to characterize the effects of mutations in a variable antibody fragment based on its expression levels, specificity, stability, and affinity for specific antigenic conserved epitopes to the Spike-S-Receptor Binding Domain (RBD). Improved contacts between Fv light and heavy chains and the targeted antigens of RBD could result in a highly potent neutralizing antibody (NAbs) response as well as cross-protection against other SARS-nCoV-2 strains. It undergoes multipoint core mutations that combine enhancing mutations, resulting in increased binding affinity and significantly increased stability between RBD and antibody. In addition, we improved. Structures of variable fragment (Fv) complexed with the RBD of Spike protein were subjected to our established in-silico antibody-engineering platform to obtain enhanced binding affinity to SARS-nCoV-2 and develop ability profiling. We found that the size and three-dimensional shape of epitopes significantly impacted the activity of antibodies produced against the RBD of Spike protein. Overall, because of the conformational changes between RBD and hACE2, it prevents viral entry. As a result of this in-silico study, the designed antibody can be used as a promising therapeutic strategy to treat COVID-19.

Discretization and Analysis of HIV-1 and HTLV-I Coinfection Model with Latent Reservoirs

This article formulates and analyzes a discrete-time Human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type I (HTLV-I) coinfection model with latent reservoirs. We consider that the HTLV-I infect the CD4(+)T cells, while HIV-1 has two classes of target cells-CD4(+)T cells and macrophages. The discrete-time model is obtained by discretizing the original continuous-time by the non-standard finite difference (NSFD) approach. We establish that NSFD maintains the positivity and boundedness of the model's solutions. We derived four threshold parameters that determine the existence and stability of the four equilibria of the model. The Lyapunov method is used to examine the global stability of all equilibria. The analytical findings are supported via numerical simulation. The impact of latent reservoirs on the HIV-1 and HTLV-I co-dynamics is discussed. We show that incorporating the latent reservoirs into the HIV-1 and HTLV-I coinfection model will reduce the basic HIV-1 single-infection and HTLV-I single-infection reproductive numbers. We establish that neglecting the latent reservoirs will lead to overestimation of the required HIV-1 antiviral drugs. Moreover, we show that lengthening of the latent phase can suppress the progression of viral coinfection. This may draw the attention of scientists and pharmaceutical companies to create new treatments that prolong the latency period.

Orf virus DNA prime-protein boost strategy is superior to adenovirus-based vaccination in mice and sheep.

Contagious ecthyma (Orf), an acute and highly contagious zoonosis, is prevalent worldwide. Orf is caused by Orf virus (ORFV), which mainly infects sheep/goats and humans. Therefore, effective and safe vaccination strategies for Orf prevention are needed. Although immunization with single-type Orf vaccines has been tested, heterologous prime-boost strategies still need to be studied. In the present study, ORFV B2L and F1L were selected as immunogens, based on which DNA, subunit and adenovirus vaccine candidates were generated. Of note, heterologous immunization strategies using DNA prime-protein boost and DNA prime-adenovirus boost in mice were performed, with single-type vaccines as controls. We have found that the DNA prime-protein boost strategy induces stronger humoral and cellular immune responses than DNA prime-adenovirus boost strategy in mice, which was confirmed by the changes in specific antibodies, lymphocyte proliferation and cytokine expression. Importantly, this observation was also confirmed when these heterologous immunization strategies were performed in sheep. In summary, by comparing the two immune strategies, we found that DNA prime-protein boost strategy can induce a better immune response, which provides a new attempt for exploring Orf immunization strategy.

Topological data analysis of antibody dynamics of severe and non-severe patients with COVID-19.

The COVID-19 pandemic is a significant public health threat with unanswered questions regarding the immune system's role in the disease's severity level. Here, based on antibody kinetic data of severe and non-severe COVID-19 patients, topological data analysis (TDA) highlights that severity is not binary. However, there are differences in the shape of antibody responses that further classify COVID-19 patients into non-severe, severe, and intermediate cases of severity. Based on the results of TDA, different mathematical models were developed to represent the dynamics between the different severity groups. The best model was the one with the lowest average value of the Akaike Information Criterion for all groups of patients. Our results suggest that different immune mechanisms drive differences between the severity groups. Further inclusion of different components of the immune system will be central for a holistic way of tackling COVID-19.

Transcriptome Profiling in Autoimmune Diseases

Autoimmune diseases are a group of different inflammatory disorders characterized by systemic or localized inflammation, affecting approximately 0.1–1% of the general population. Several studies suggest that genetic risk loci are shared between different autoimmune diseases and pathogenic mechanisms may also be shared. The strategy of performing differential gene expression profiles in autoimmune disorders has unveiled new transcripts that may be shared among these disorders. Microarray technology and bioinformatics offer the most comprehensive molecular evaluations and it is widely used to understand the changes in gene expression in specific organs or in peripheral blood cells. The major goal of transcriptome studies is the identification of specific biomarkers for different diseases. It is believed that such knowledge will contribute to the development of new drugs, new strategies for early diagnosis, avoiding tissue autoimmune destruction, or even preventing the development of autoimmune disease. In this review, we primarily focused on the transcription profiles of three typical autoimmune disorders, including type 1 diabetes mellitus (destruction of pancreatic islet beta cells), systemic lupus erythematosus (immune complex systemic disorder affecting several organs and tissues), and multiple sclerosis (inflammatory and demyelinating disease of the nervous system). © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2014, 2022.

Antiviral Nanobiologic Therapy Remodulates Innate Immune Responses to Highly Pathogenic Coronavirus.

Highly pathogenic coronavirus (CoV) infection induces a defective innate antiviral immune response coupled with the dysregulated release of proinflammatory cytokines and finally results in acute respiratory distress syndrome (ARDS). A timely and appropriate triggering of innate antiviral response is crucial to inhibit viral replication and prevent ARDS. However, current medical countermeasures can rarely meet this urgent demand. Here, an antiviral nanobiologic named CoVR-MV is developed, which is polymerized of CoVs receptors based on a biomimetic membrane vesicle system. The designed CoVR-MV interferes with the viral infection by absorbing the viruses with maximized viral spike target interface, and mediates the clearance of the virus through its inherent interaction with macrophages. Furthermore, CoVR-MV coupled with the virus promotes a swift production and signaling of endogenous type I interferon via deregulating 7-dehydrocholesterol reductase (DHCR7) inhibition of interferon regulatory factor 3 (IRF3) activation in macrophages. These sequential processes re-modulate the innate immune responses to the virus, trigger spontaneous innate antiviral defenses, and rescue infected Syrian hamsters from ARDS caused by SARS-CoV-2 and all tested variants.

More than a key-the pathological roles of SARS-CoV-2 spike protein in COVID-19 related cardiac injury.

Cardiac injury is common in hospitalized coronavirus disease 2019 (COVID-19) patients and cardiac abnormalities have been observed in a significant number of recovered COVID-19 patients, portending long-term health issues for millions of infected individuals. To better understand how Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, CoV-2 for short) damages the heart, it is critical to fully comprehend the biology of CoV-2 encoded proteins, each of which may play multiple pathological roles. For example, CoV-2 spike glycoprotein (CoV-2-S) not only engages angiotensin converting enzyme II (ACE2) to mediate virus infection but also directly activates immune responses. In this work, the goal is to review the known pathological roles of CoV-2-S in the cardiovascular system, thereby shedding lights on the pathogenesis of COVID-19 related cardiac injury.