The world has responded to the COVID-19 pandemic with unprecedented speed and vigor in the mass vaccination campaigns, targeted to reduce COVID-19 severity and mortality, reduce the pressure on the healthcare system, re-open society, and reduction in disease mortality and morbidity. Here we review the preclinical and clinical development of BBV152, a whole virus inactivated vaccine and an important tool in the fight to control this pandemic. BBV152, formulated with a TLR7/8 agonist adjuvant generates a Th1-biased immune response that induces high neutralization efficacy against different SARS-CoV-2 variants of concern and robust long-term memory B- and T-cell responses. With seroconversion rates as high as 98.3% in vaccinated individuals, BBV152 shows 77.8% and 93.4% protection from symptomatic COVID-19 disease and severe symptomatic COVID-19 disease respectively. Studies in pediatric populations show superior immunogenicity (geometric mean titer ratio of 1.76 compared to an adult) with a seroconversion rate of >95%. The reactogenicity and safety profiles were comparable across all pediatric age groups between 2-18 yrs. as in adults. Like most approved vaccines, the BBV152 booster given 6 months after full vaccination, reverses a waning immunity, restores the neutralization efficacy, and shows synergy in a heterologous prime-boost study with about 3-fold or 300% increase in neutralization titers against multiple SARS-CoV-2 variants of concern. Based on the interim Phase III data, BBV152 received full authorization for adults and emergency use authorization for children from ages 6 to 18 years in India. It is also licensed for emergency use in 14 countries globally. Over 313 million vaccine doses have already been administered in India alone by April 18th, 2022.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and recently has become a serious global pandemic. Age, gender, and comorbidities are known to be common risk factors for severe COVID-19 but are not enough to fully explain the magnitude of their effect on the risk of severity of the disease. Single nucleotide polymorphisms (SNPs) in several genes have been reported as a genetic factor contributing to COVID-19 severity. This comprehensive review focuses on the association between SNPs in four important genes and COVID-19 severity in a global aspect. We discuss a total of 39 SNPs in this review: five SNPs in the ABO gene, nine SNPs in the angiotensin-converting enzyme 2 (ACE2) gene, 19 SNPs in the transmembrane protease serine 2 (TMPRSS2) gene, and six SNPs in the toll-like receptor 7 (TLR7) gene. These SNPs data could assist in monitoring an individual\'s risk of severe COVID-19 disease, and therefore personalized management and pharmaceutical treatment could be planned in COVID-19 patients.

Coronavirus disease 2019 (COVID-19) has spread rapidly and become a pandemic. Caused by a novel human coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe COVID-19 is characterized by cytokine storm syndromes due to innate immune activation. Primary immunodeficiency (PID) cases represent a special patient population whose impaired immune system might make them susceptible to severe infections, posing a higher risk to COVID-19, but this could also lead to suppressed inflammatory responses and cytokine storm. It remains an open question as to whether the impaired immune system constitutes a predisposing or protective factor for PID patients when facing SARS-CoV-2 infection. After literature review, it was found that, similar to other patient populations with different comorbidities, PID patients may be susceptible to SARS-CoV-2 infection. Their varied immune status, however, may lead to different disease severity and outcomes after SARS-CoV-2 infection. PID patients with deficiency in antiviral innate immune signaling [eg, Toll-like receptor (TLR)3, TLR7, or interferon regulatory factor 7 (IRF7)] or interferon signaling (IFNAR2) may be linked to severe COVID-19. Because of its anti-infection, anti-inflammatory, and immunomodulatory effects, routine intravenous immunoglobulin therapy may provide some protective effects to the PID patients.

BACKGROUND: Toll-like receptors 7 and 8 (TLR7 and TLR8) are endosomal immune receptors that initiate an innate immune response and can facilitate activation of the adaptive immune system. Both preclinical and clinical studies have shown the downstream inflammatory response from TLR7 and TLR8 agonism results in preliminary efficacy for the treatment of cancer, viral infections, and for use as a vaccine adjuvant.
UNASSIGNED: This patent review covers recent developments in small molecule TLR7 and TLR8 agonists published between January 2014 - February 2020. We summarize relevant chemical scaffolds, observed structure-activity relationships, and where available, preliminary animal models, and clinical data.
UNASSIGNED: In the last 6 years, there has been significant progress in the optimization of novel TLR7 and TLR8 small molecule agonists. These novel compounds are currently being evaluated in the clinic for multiple antiviral and oncology indications. Clinical data from these trials will provide a clearer outlook on 1) the TLR7/8 engagement necessary to obtain the desired immune response, 2) safety margin improvement using directed delivery, and 3) potential synergistic effects with checkpoint inhibitor combination therapies.

Head and neck squamous cell carcinoma (HNSCC) is a group of tumours which exhibit low 5 year survival rates. Thus, there is an urgent need to identify biomarkers that may improve the clinical utility of patients with HNSCC. Emerging studies support a role of toll-like receptors (TLRs) in carcinogenesis. Therefore, this systematic review and meta-analysis was performed to assess the prognostic value of TLR immunoexpression in HNSCC patients. We compiled the results of thirteen studies comprising 1825 patients, of which six studies were deemed qualified for quantitative synthesis. The higher immunoexpression of TLR-1 to 5 and 9 was associated with a worsening of the clinical parameters of patients with HNSCC. Furthermore, induced levels of TLR-3, 4, 5, 7 and 9 were found to predict the patients\' survival time. The meta-analysis revealed that TLR-7 overexpression is associated with a decreased mortality risk in HNSCC patients (HR 0.51; 95%CI 0.13-0.89; I2 34.6%), while a higher expression of TLR-5 predicted shorter, but non-significant, survival outcome. In conclusion, this review suggests that TLRs may represent some prognostic value for patients with HNSCC. However, due to small sample sizes and other inherent methodological limitations, more well designed studies across different populations are still needed before TLRs can be recommended as a reliable clinical risk-stratification tool.

The 2015 Conference on Retroviruses and Opportunistic Infections (CROI) represents a forum that encompasses all facets of research on HIV/AIDS and its complications. CROI is a valuable venue for scientific and public health researchers, clinicians, policy makers, and community representatives to be updated on the latest advances in their specific areas of interest and beyond. CROI 2015 continued to surprise. New insights into the viral reservoirs that persist in the face of antiretroviral therapy were prominently featured, as were therapeutic approaches aimed at curtailing and eliminating persistent viral reservoirs in HIV-infected individuals. Basic science is providing surrogates that could be valuable in how viral reservoirs are measured and, ultimately, in how to gauge if they are being effectively eliminated.

The aim of this study was to determine whether toll-like receptor (TLR) polymorphisms confers susceptibility to vasculitis. A literature search was conducted using the PubMed and Embase. A meta-analysis on the associations between the TLR4 Asp299Gly polymorphisms and vasculitis was carried out using allele contrast, dominant, and codominant models and a systematic review of other TLR polymorphisms. Fourteen studies involving 2,064 patients and 2,481 controls were included in this systematic review, which comprised nine on Behcet\'s disease (BD), three on giant cell arteritis (GCA), and one on Henoch-Schenlein purpura (HSP). Meta-analysis of six studies showed a significant association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis and GCA (Odds ratio [OR] = 1.368, 95 % confidence interval [CI] = 1.300-1.815, p = 0.030; OR = 1.523, 95 % CI = 1.099-2.112, p = 0.012). Under a random effects model, the adjusted ORs calculated using the trim and fill technique revealed an association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis (OR = 1.544, 95 % CI = 1.091-2.185, p < 0.05). Stratification by vasculitis type using the codominant model showed the trend for the association with GCA (OR = 1.569, 95 % CI = 0.970-2.538, p = 0.066). There were three studies on the TLR2 Arg753Gln polymorphism and two on the TLR4 Thr399Ile polymorphism; no association with vasculitis was evident. Among the TLR2, TLR7, and TLR9 polymorphisms included in this review, one Asian study revealed a significant association between the TLR7 rs5743733 and rs3853839 with BD (p = 0.002, 0.036) and one Asian study showed an association of TLR9 rs352140 with BD (p = 0.009). This meta-analysis demonstrates that the TLR4 Asp299Gly polymorphism may confer susceptibility to GCA. The review of published data suggests that other TLR polymorphisms such as TLR7 and TLR9 may play a role in vasculitis.

OBJECTIVE: The aim of this study was to determine whether the polymorphisms of Toll-like receptor (TLR) confer susceptibility to systemic lupus erythematosus (SLE).
METHODS: The authors conducted a systematic review and meta-analysis of reports on associations between TLR polymorphisms and SLE susceptibility.
RESULTS: A total of 8 studies (11 separate comparisons) were included in this meta-analysis, which included European and Asian populations. Metaanalysis showed an association between the 2 allele of rs3853839 (TLR7) and SLE in Asian subjects (OR 1.246; 95% CI 1.160, 1.388; p=2×10-9). No studies on rs3853839 (TLR7) and rs352139 (TLR9) have been performed in Europeans. No association was found between SLE and the 2 alleles of the rs5743836 (TLR9) polymorphism in all overall subjects or in Europeans, but one study showed a significant association in Asians (OR 4.243; 95% CI 1.487, 12.10; p=0.007). Furthermore, no association was found between the rs5744168 (TLR5) polymorphism and SLE susceptibility in Europeans or between the rs187084 (TLR8) or rs352140 (TLR9) polymorphisms and SLE susceptibility in Asians.
CONCLUSIONS: This meta-analysis suggests that the TLR7 and TLR9 polymorphisms are associated with the development of SLE in Asians. Further studies are required to determine whether the TLR polymorphisms contribute to SLE susceptibility in other ethnic groups.

The immunomodulatory characteristics and topical application of imiquimod (IQ), a toll-like receptor 7 agonist, have lead to extensive off-label therapeutic trials. Off-label use is not uncommon in dermatology. However, clinicians must make informed decisions to ensure safe and effective implementation when standardized protocols are lacking. We present the highest level of clinical evidence for each off-label application of IQ, summarize management steps, treatment regimens, and results. We hope consolidation of this information will facilitate implementation of informed and evidence-based clinical decisions. Forty-six off-label applications were reported. Treatments were generally applied in the same manner, tailored to induce an inflammatory response and reduced with the development of adverse reactions. The efficacy of imiquimod ranged from promising to suboptimal compared to standard treatments and protocols. Clinicians who choose to use IQ off-label should have a firm understanding of the extent an application has been studied and how to manage adverse events.

We review the systemic lupus erythematosus (SLE) human genetics literature, including the first wave of genome-wide associations scans (GWAS), to identify confirmed and candidate risk variants that meet stringent statistical criteria. The understanding of the genetic basis of SLE in humans has expanded dramatically over the past year, offering an early glimpse into the primary genetic factors and major dysregulated pathways. A meta-analysis of published candidate variants was performed incorporating data from a 1310 case and 7859 control GWAS. Our review of the literature and meta-analysis identifies a total of 17 well-validated common SLE risk variants, including four candidate variants that achieve our definition of a confirmed SLE risk locus. These variants account for a fraction of the total genetic contribution to SLE risk, with many risk loci remaining to be identified, but may provide insight into the pathways involved in SLE. Initial pathway analyses of the 17 confirmed SLE risk alleles indicate an important role for B-cell signalling and development, signaling through toll-like receptors 7 and 9, and neutrophil function.