Vaccine Efficacy, Impact, Hesitancy, and Acceptance: Trends for Public Health.

Vaccines are indispensable tools in the battle against infectious diseases and hold great potential in combating a myriad of other diseases [...].

Association of the Magnitude of Anti-SARS-CoV-2 Vaccine Side Effects with Sex, Allergy History, Chronic Diseases, Medication Intake, and SARS-CoV-2 Infection.

Vaccination provides the best protection against the increasing infections of SARS-CoV-2. The magnitude and type of anti-SARS-CoV-2 vaccine side effects (SEs) depend on parameters that are not fully understood. In this cross-sectional study, the associations between different anti-SARS-CoV-2 vaccine SEs and age, sex, the presence of chronic diseases, medication intake, history of allergies, and infections with SARS-CoV-2 were investigated. Our survey used the Google platform and had 866 participants, contacted through e-mails, social media and chain referral sampling (margin of error ≈ 4.38%, 99% confidence). More than 99% of the participants received the BNT162b2 and ChAdOx1-S vaccines. Being female, having chronic diseases, taking medicines routinely and the presence of a SARS-CoV-2 infection (p < 0.05) were associated with strong SEs after the BNT162b2 vaccine second dose. Having a history of allergies and a female sex (p < 0.01) were associated with strong SEs after the ChAdOx1-S vaccine second dose. Furthermore, the results reveal, for the first time, the associations between having a history of allergies, chronic diseases, medication usage, and SEs of a strong magnitude for the BNT162b2 and ChAdOx1-S vaccines. Additionally, this study supports the association of the female sex and infection with SARS-CoV-2 with an increased potential of developing stronger SEs with certain anti-SARS-CoV-2 vaccines.

Differential Production of Midkine and Pleiotrophin by Innate APCs upon Stimulation through Nucleic Acid-Sensing TLRs.

Midkine (MK) and pleiotrophin (PTN) belong to the same family of cytokines. They have similar sequences and functions. Both have important roles in cellular proliferation, tumors, and diseases. They regulate and are expressed by some immune cells. We have recently demonstrated MK production by some human innate antigen-presenting cells (iAPCs), i.e., monocyte-derived dendritic cells (MDDCs) and macrophages stimulated through Toll-like receptor (TLR)-4, and plasmacytoid dendritic cells (pDCs) stimulated through TLR 7. While PTN production was only documented in tissue macrophages. TLRs 3, 7, 8, and 9 are nucleic acid sensing (NAS) TLRs that detect nucleic acids from cell damage and infection and induce iAPC responses. We investigated whether NAS TLRs can induce MK and PTN production by human iAPCs, namely monocytes, macrophages, MDDCs, myeloid dendritic cells (mDCs), and pDCs. Our results demonstrated for the first time that PTN is produced by all iAPCs upon TLR triggering (p < 0.01). IAPCs produced more PTN than MK (p < 0.01). NAS TLRs and iAPCs had differential abilities to induce the production of MK, which was induced in monocytes and pDCs by all NAS TLRs (p < 0.05) and in MDDCs by TLRs 7/8 (p < 0.05). TLR4 induced a stronger MK production than NAS TLRs (p ≤ 0.05). Monocytes produced higher levels of PTN after differentiation to macrophages and MDDCs (p < 0.05). The production of MK and PTN differs among iAPCs, with a higher production of PTN and a selective induction of MK production by NAS TLR. This highlights the potentially important role of iAPCs in angiogenesis, tumors, infections, and autoimmunity through the differential production of MK and PTN upon TLR triggering.

Circadian Rhythm, Sleep, and Immune Response and the Fight against COVID-19.

Sleep is an imperative physiological aspect that plays a vital role in maintaining hormonal and humeral functions of the body and hence a healthy life. Circadian rhythms are daily oscillations in human activities and physiology that prepare human beings to better react to and anticipate challenges in the surrounding environment, which are a consequence of diurnal changes of day and night. The sleep/wake cycle is one of the most prominent manifestations of the circadian rhythm and communicates tightly with the immune system with daily oscillation of immunity. Sleep deprivation is now recognized as a common condition inherent to modern society, and it is detrimental to certain body functions, particularly immune function. The aim of this review is to explore the role of sleep in maintaining a healthy immune system during the COVID-19 pandemic. The review discusses sleep-regulatory substances that are linked to host defense mechanisms such as interleukin-1ß, interleukin-6, tumor necrosis factor alpha, and interferon gamma. Cytokine levels also fluctuate with sleep/wake homeostasis and our review explores the relationship between sleep and cytokines and proposed therapeutics. The review will also cover sleep and immune response in children, adolescents, and healthcare workers, and finally it will touch on the effect of obstructive sleep apnea on immune response and the severity of COVID-19.

Human macrophages and monocyte-derived dendritic cells stimulate the proliferation of endothelial cells through midkine production.

The cytokine midkine (MK) is a growth factor that is involved in different physiological processes including tissue repair, inflammation, the development of different types of cancer and the proliferation of endothelial cells. The production of MK by primary human macrophages and monocyte-derived dendritic cells (MDDCs) was never described. We investigated whether MK is produced by primary human monocytes, macrophages and MDDCs and the capacity of macrophages and MDDCs to modulate the proliferation of endothelial cells through MK production. The TLR stimulation of human monocytes, macrophages and MDDCs induced an average of ≈200-fold increase in MK mRNA and the production of an average of 78.2, 62, 179 pg/ml MK by monocytes, macrophages and MDDCs respectively (p < 0.05). MK production was supported by its detection in CD11c+ cells, CLEC4C+ cells and CD68+ cells in biopsies of human tonsils showing reactive lymphoid follicular hyperplasia. JSH-23, which selectively inhibits NF-κB activity, decreased the TLR-induced production of MK in PMBCs, macrophages and MDDCs compared to the control (p < 0.05). The inhibition of MK production by macrophages and MDDCs using anti-MK siRNA decreased the capacity of their supernatants to stimulate the proliferation of endothelial cells (p = 0.01 and 0.04 respectively). This is the first study demonstrating that the cytokine MK is produced by primary human macrophages and MDDCs upon TLR triggering, and that these cells can stimulate endothelial cell proliferation through MK production. Our results also suggest that NF-κB plays a potential role in the production of MK in macrophages and MDDCs upon TLR stimulation. The production of MK by macrophages and MDDCs and the fact that these cells can enhance the proliferation of endothelial cells by producing MK are novel immunological phenomena that have potentially important therapeutic implications.

Effects of Bacterial Metabolites on the Immune System: Enemies and Friends.

Metabolites produced by bacteria can influence the immune system. These metabolites are produced by pathogenic bacteria as well as the friendly microbiota. This review sheds light on the major bacterial metabolites and their structures. It also describes the capacity of these molecules to stimulate and inhibit the immune responses in a way that affects their capacity to control different diseases.

Prevalence and persistence of SARS-CoV2 antibodies among healthcare workers in Oman.

OBJECTIVES: The primary objective is to determine the prevalence of SARS-CoV-2 antibodies persistence among HCWs and specifically among asymptomatic HCWs. A secondary objective is to determine the duration of persistent SARS-CoV-2 antibodies post infection and factors affecting this duration. The findings are expected to open the door for further research into the role of SARS-CoV-2 antibodies during the current COVID-19 pandemic. METHODOLOGY: HCWs were divided into high, intermediate, and low risk based on their type and location of work. All participants filled a questionnaire. Blood samples were obtained for SARS-CoV-2 IgG/total antibodies. A documented SARS-CoV-2 PCR or Anti-SARS-CoV-2 IgG/total antibodies defined the primary outcome. The probability of persistence of antibody was calculated using the Kaplan-Meier estimator. Logistic and Cox regression were used where appropriate. RESULTS: A total of 1111 HCWs were included. The median age 37 years (IQR: 31-43). More than half (67.2%) were females. The primary outcome was seen in 373 (33.6%) participants with a median age of 36 years (IQR: 29-41). Only 37.2% of those with documented positive SARS-CoV-2 PCR had reactive serology, while only 16.2% of those with reactive serology had documented positive SARS-CoV-2 PCR. Male gender (OR 0.44, P < 0.001) and older age (OR 0.98, P < 0.019) were associated with a lower risk of acquiring SARS-CoV-2 infection. The probability of persistent SARS-CoV-2 antibodies at six months was 60.2% (95% CI: 49.5%-73.1%). Omanis had a higher probability of losing the antibody than others (HR 2.63, P = 0.021). CONCLUSION: We report a high prevalence of anti-SARS-CoV-2 antibodies among HCWs in Oman, specifically among asymptomatic HCWs. Community was the most likely source of infection. Therefore, the society must adhere to the roles and regulations set to reduce the risk of transmission. We demonstrate a high percentage of seroconversion post initial infection, and the persistence of SARS-CoV-2 antibodies at six months in more than half of those previously infected. We demonstrated a new interesting finding of fast decline of SARS-CoV2 antibody levels over time among different nationalities and this requires further research.

Defining IL-6 levels in healthy individuals: A meta-analysis.

BACKGROUND: Interleukin-6 (IL-6) is produced by and impacts different cell types in human. IL-6 is associated with different diseases and viral infections, including COVID-19. To our knowledge, no normal values were reported for IL-6 in the blood of healthy individuals. We have reviewed and performed a meta-analysis on a total of 140 studies, including 12,421 values for IL-6 in the blood of healthy adult donors. Among these studies, 83 did not report a mean value and the standard deviation. Therefore, for the statistical analysis, we used the values reported in 57 studies, which included 3166 values for IL-6. RESULTS: The reported values for IL-6 in the blood of healthy donors varied between 0 and 43.5 pg/ml. The pooled estimate of IL-6 was 5.186 pg/ml (95% confidence interval [CI]: 4.631, 5.740). As the age increased by 1 year, IL-6 values increased by 0.05 pg/ml (95% CI: 0.02, 0.09; p < .01). Though the heterogenicity, as determined by I2 statistics, was high in our study, the differences in IL-6 values are still at the level of a few pg/ml, which might be related to the differences in the conditions that influence IL-6 production in the healthy population. CONCLUSIONS: This is the first meta-analysis reporting the levels of IL-6 in the blood of healthy donors based on a large number of studies and donors. Therefore the 95% CI values determined in our study could well serve as a reference range for quick decision-making in clinical interventions, particularly those aiming to inhibit IL-6, especially urgent interventions, for example, COVID-19.

Sleep deprivation alters neutrophil functions and levels of Th1-related chemokines and CD4+ T cells in the blood.

PURPOSE: The state of knowledge about the effect of sleep deprivation on the immune system is scarce and conflicting. It would therefore be useful to investigate the consequences of sleep deprivation on the immune system. We have studied the effect of sleep deprivation on the changes in neutrophil functions, and the ex vivo proliferative pattern of CD4+ T lymphocytes in relationship with blood cytokine and chemokine levels due to the crucial role of these cells in mounting potent immune responses. METHODS: Healthy volunteers were followed for 3 weeks. They had normal sleep in weeks 1 and 3 and they were sleep-deprived on week 2, sleeping < 6 h per 24 h, a pattern similar to sleep behaviors of many chronically sleep-deprived individuals. We assessed the levels of Th1/Th2 and inflammatory cytokines and chemokines, CD4+ T cells, and the NADPH oxidase activation and phagocytic functions in neutrophils. RESULTS: Our results suggest that sleep deprivation leads to a decreased neutrophil capacity to phagocytose bacteria and activate NADPH oxidase (p < 0.05). Sleep deprivation was associated with a potential increase in CXCL9 levels and decrease in CXCL10/CXCL9 and CCL5/CXCL9 ratios (p < 0.05). Furthermore, our results suggest that the decrease in CD4+ T cell due to sleep deprivation was not associated with changes in their proliferation as observed by Ki67 levels, but rather, it correlated with changes in CXCL10/CXCL9 ratio (p < 0.05). CONCLUSIONS: Sleep deprivation may lead to a decreased phagocytosis and NADPH oxidase activity in neutrophils and a decrease in the levels of CD4+ T cells which is related to changes in the Th1-related chemokine balance.

Viruses Seen by Our Cells: The Role of Viral RNA Sensors.

The role of the innate immune response in detecting RNA viruses is crucial for the establishment of proper inflammatory and antiviral responses. Different receptors, known as pattern recognition receptors (PRRs), are present in the cytoplasm, endosomes, and on the cellular surface. These receptors have the capacity to sense the presence of viral nucleic acids as pathogen-associated molecular patterns (PAMPs). This recognition leads to the induction of type 1 interferons (IFNs) as well as inflammatory cytokines and chemokines. In this review, we provide an overview of the significant involvement of cellular RNA helicases and Toll-like receptors (TLRs) 3, 7, and 8 in antiviral immune defenses.

Altered blood cytokines, CD4 T cells, NK and neutrophils in patients with obstructive sleep apnea.

BACKGROUND: There are contradictory reports on the effects of obstructive sleep apnea (OSA) on the immune system. In order to clarify the effect of OSA on the different components of the immune system, we studied the association of OSA with changes in cytokine and chemokine levels, proliferative patterns of CD4 and CD8 T lymphocytes as well as NK cells ex vivo and neutrophil functions. METHODS: We investigated the association of OSA with potential alterations in 14 Th1/Th2 and inflammatory cytokines and chemokines, CD4 and CD8 T cells, NK cells, and the NADPH oxidase activation and phagocytic functions in neutrophils. RESULTS: Our results suggest that the increase in CD4 T cell frequency in OSA is associated with an increased expression of the nuclear protein Ki67 (p<0.05; power>0.8), and is correlated with the levels of IL-1ß (p<0.05; power>0.8). The levels of IL-1ß as well as IL-6 showed a potential increase, while the levels of IFN-γ (p<0.05; power>0.8) and the ratio IFN-γ/IL-4 in the blood were possibly decreased in OSA. Additionally, we observed a potential increase in the expression of Ki67 in CD8hi and CD8lo NK cells (p<0.05; power>0.8). Our results also suggest that neutrophils have a decreased capacity to phagocytose bacteria and activate NADPH oxidase in OSA patients (p<0.05; power>0.8). CONCLUSION: OSA may be associated with inflammatory and pro-Th2 immune responses, an increased proliferative potential of NK and CD4 T cells and a decreased capacity of neutrophils to phagocytose bacteria and produce ROS.

HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses.

The innate and adaptive immune systems fail to control HCV infection in the majority of infected individuals. HCV is an ssRNA virus, which suggests a role for Toll-like receptors (TLRs) 7 and 8 in initiating the anti-viral response. Here we demonstrate that HCV genomic RNA harbours specific sequences that initiate an anti-HCV immune response through TLR7 and TLR8 in various antigen presenting cells. Conversely, HCV particles are detected by macrophages, but not by monocytes and DCs, through a TLR7/8 dependent mechanism; this leads to chloroquine sensitive production of pro-inflammatory cytokines including IL-1ß, while the antiviral type I Interferon response is not triggered in these cells. Antibodies to DC-SIGN, a c-type lectin selectively expressed by macrophages but not pDCs or mDCs, block the production of cytokines. Novel anti-HCV vaccination strategies should target the induction of TLR7/8 stimulation in APCs in order to establish potent immune responses against HCV.

Increased CD86 but Not CD80 and PD-L1 Expression on Liver CD68+ Cells during Chronic HBV Infection.

BACKGROUND: The failure to establish potent anti-HBV T cell responses suggests the absence of an effective innate immune activation. Kupffer cells and liver-infiltrating monocytes/macrophages have an essential role in establishing anti-HBV responses. These cells express the costimulatory molecules CD80 and CD86. CD80 expression on antigen-presenting cells (APCs) induces Th1 cell differentiation, whereas CD86 expression drives the differentiation towards a Th2 profile. The relative expression of CD80, CD86 and PD-L1 on APCs, regulates T cell activation. Few studies investigated CD80 and CD86 expression on KCs and infiltrating monocytes/macrophages in HBV-infected liver and knowledge about the expression of PD-L1 on these cells is controversial. The expression of these molecules together in CD68+ cells has not been explored in HBV-infected livers. METHODS: Double staining immunohistochemistry was applied to liver biopsies of HBV-infected and control donors to explore CD80, CD86 and PD-L1 expression in the lobular and portal areas. RESULTS: Chronic HBV infection was associated with increased CD68+CD86+ cell count and percentage in the lobular areas, and no changes in the count and percentage of CD68+CD80+ and CD68+PD-L1+ cells, compared to the control group. While CD68+CD80+ cell count in portal areas correlated with the fibrosis score, CD68+CD80+ cell percentage in lobular areas correlated with the inflammation grade. CONCLUSION: The upregulation of CD86 but not CD80 and PD-L1 on CD68+ cells in HBV-infected livers, suggests that these cells do not support the induction of potent Th1. Moreover, the expression of CD80 on CD68+ cells correlates with liver inflammation and fibrosis.

A Potential Inhibitory Profile of Liver CD68+ Cells during HCV Infection as Observed by an Increased CD80 and PD-L1 but Not CD86 Expression.

AIM: The lack of potent innate immune responses during HCV infection might lead to a delay in initiating adaptive immune responses. Kupffer cells (KCs) and liver-infiltrating monocytes/macrophages (CD68+ cells) are essential to establish effective anti-HCV responses. They express co-stimulatory molecules, CD80 and CD86. CD86 upregulation induces activator responses that are then potentially regulated by CD80. The relative levels of expression of CD80, CD86 and the inhibitory molecule, PD-L1, on CD68+ cells modulate T cell activation. A few studies have explored CD80 and PD-L1 expression on KCs and infiltrating monocytes/macrophages in HCV-infected livers, and none investigated CD86 expression in these cells. These studies have identified these cells based on morphology only. We investigated the stimulatory/inhibitory profile of CD68+ cells in HCV-infected livers based on the balance of CD80, CD86 and PD-L1 expression. METHODS: CD80, CD86 and PD-L1 expression by CD68+ cells in the lobular and portal areas of the liver of chronic HCV-infected (n = 16) and control (n = 14) individuals was investigated using double staining immunohistochemistry. RESULTS: The count of CD68+ KCs in the lobular areas of the HCV-infected livers was lower than that in the control (p = 0.041). The frequencies of CD68+CD80+ cells and CD68+PD-L1+ cells in both lobular and total areas of the liver were higher in HCV-infected patients compared with those in the control group (p = 0.001, 0.031 and 0.007 respectively). Moreover, in the lobular areas of the HCV-infected livers, the frequency of CD68+CD80+ cells was higher than that of CD68+CD86+ and CD68+PD-L1+ cells. In addition, the frequencies of CD68+CD80+ and CD68+CD86+ cells were higher in the lobular areas than the portal areas. CONCLUSIONS: Our results show that CD68+ cells have an inhibitory profile in the HCV-infected livers. This might help explain the delayed T cell response and viral persistence during HCV infection.

Nef promotes evasion of human immunodeficiency virus type 1-infected cells from the CTLA-4-mediated inhibition of T-cell activation.

CTLA-4 is a negative regulator of T-cell receptor-mediated CD4(+) T-cell activation and function. Upregulation of CTLA-4 during human immunodeficiency virus type 1 (HIV-1) infection on activated T cells, particularly on HIV-specific CD4(+) T cells, correlates with immune dysfunction and disease progression. As HIV-1 infects and replicates in activated CD4(+) T cells, we investigated mechanisms by which HIV-1 modulates CTLA-4 expression to establish productive viral infection in these cells. Here, we demonstrate that HIV-1 infection in activated CD4(+) T cells was followed by Nef-mediated downregulation of CTLA-4. This was associated with a decreased T-cell activation threshold and significant resistance to CTLA-4 triggering. In line with these in vitro results, quantification of pro-viral HIV DNA from treatment-naive HIV-infected subjects demonstrated a preferential infection of memory CD4(+)CTLA-4(+) T cells, thus identifying CTLA-4 as a biomarker for HIV-infected cells in vivo. As transcriptionally active HIV-1 and Nef expression in vivo were previously shown to take place mainly in the CD3(+)CD4(-)CD8(-) [double-negative (DN)] cells, we further quantified HIV DNA in the CTLA-4(+) and CTLA-4(-) subpopulations of these cells. Our results showed that DN T cells lacking CTLA-4 expression were enriched in HIV DNA compared with DN CTLA-4(+) cells. Together, these results suggested that HIV-1 preferential infection of CD4(+)CTLA-4(+) T cells in vivo was followed by Nef-mediated concomitant downregulation of both CD4 and CTLA-4 upon transition to productive infection. This also highlights the propensity of HIV-1 to evade restriction of the key negative immune regulator CTLA-4 on cell activation and viral replication, and therefore contributes to the overall HIV-1 pathogenesis.

Fluctuation in the Levels of Immunoglobulin M and Immunoglobulin G Antibodies for Cardiolipin and ß2-Glycoprotein among Healthy Pregnant Women.

OBJECTIVES: Antiphospholipid antibodies fluctuate during a healthy normal pregnancy. This study aimed to investigate the levels of both immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies for cardiolipin and ß2-glycoprotein (ß2GP) among healthy pregnant women. METHODS: This study was conducted between May 2010 and December 2012. A total of 75 healthy Omani pregnant women with no history of autoimmune disease were investigated during their pregnancy and 90 days after delivery at the Armed Forces Hospital in Muscat, Oman. A control group of 75 healthy Omani non-pregnant women were also investigated as a comparison. Levels of IgM and IgG antibodies for both anti-cardiolipin antibodies (ACAs) and ß2GP were measured using a standard enzyme-linked immunosorbent assay. RESULTS: The ACA IgM levels were significantly higher in the control group compared to the pregnant women (P <0.001). No significant differences were observed in the ACA IgM levels between the control group and the pregnant women after delivery. In contrast, ACA IgG levels were significantly higher during pregnancy and after delivery compared with those of the healthy control group (P = 0.007 and 0.002, respectively). The levels of ß2GP IgG were significantly higher during pregnancy than after delivery and in the control group (P = 0.001 and <0.001, respectively). CONCLUSION: In this study, ACA IgG levels increased during healthy pregnancies and after normal deliveries whereas ß2GP IgG levels increased transiently during the pregnancies. Both phenomena were found to be significantly associated with a transient decline in the levels of IgM specific for these antigens. Therefore, the levels of these antibodies may be regulated during a healthy pregnancy.

Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis.

Loss of memory B cells occurs from the onset of HIV-1 infection and persists into the chronic stages of infection. Lack of survival of these cells, even in subjects being treated, could primarily be the consequence of an altered local microenvironment induced by HIV infection. In this study we showed that memory B cell survival was significantly decreased in aviremic successfully treated (ST) subjects compared with subjects who control viral load as a result of natural immunity (elite controller [EC]) or with uninfected control (HIV-) subjects. The lower survival levels observed in memory B cells from ST subjects were the result of disrupted IL-2 signaling that led to increased transcriptional activity of Foxo3a and increased expression of its proapoptotic target TRAIL. Notably, memory B cell survival in ST subjects was significantly enhanced by the addition of exogenous IL-2 in a Foxo3a-dependent manner. We further showed that Foxo3a silencing by siRNA resulted in decreased expression of TRAIL and apoptosis levels in memory B cells from ST subjects. Our results thus establish a direct role for Foxo3a/TRAIL signaling in the persistence of memory B cells and provide a mechanism for the reduced survival of memory B cells during HIV infection. This knowledge could be exploited for the development of therapeutic and preventative HIV vaccines.