The journey of a lifetime - development of Pfizer's COVID-19 vaccine.

It would be apt to say that one of the greatest accomplishments in modern medicine has been the development of vaccines against COVID-19, which had paralyzed the entire world for more than a year. Pfizer and BioNTech codeveloped the first COVID-19 vaccine that was granted emergency-use authorization or conditional approval in several regions globally. This article is an attempt to go 'behind-the-scenes' of this development process and highlight key factors that allowed us to move with this unprecedented speed, while adhering to normal vaccine-development requirements to generate the information the regulatory authorities needed to assess the safety and effectiveness of a vaccine to prevent an infectious disease, including quality and manufacturing standards. This is also a story of how Pfizer and BioNTech leveraged our combined skill sets and experience to respond to the global health crisis to progress this program swiftly while ensuring the compliance with our high-quality standards and keeping patient safety at the forefront. We will also highlight multiple other factors that were instrumental in our success.

Bioactivity and In Silico Studies of Isoquinoline and Related Alkaloids as Promising Antiviral Agents: An Insight.

Viruses are widely recognized as the primary cause of infectious diseases around the world. The ongoing global pandemic due to the emergence of SARS-CoV-2 further added fuel to the fire. The development of therapeutics becomes very difficult as viruses can mutate their genome to become more complex and resistant. Medicinal plants and phytocompounds could be alternative options. Isoquinoline and their related alkaloids are naturally occurring compounds that interfere with multiple pathways including nuclear factor-κB, mitogen-activated protein kinase/extracellular-signal-regulated kinase, and inhibition of Ca2+-mediated fusion. These pathways play a crucial role in viral replication. Thus, the major goal of this study is to comprehend the function of various isoquinoline and related alkaloids in viral infections by examining their potential mechanisms of action, structure-activity relationships (SAR), in silico (particularly for SARS-CoV-2), in vitro and in vivo studies. The current advancements in isoquinoline and related alkaloids as discussed in the present review could facilitate an in-depth understanding of their role in the drug discovery process.

In silico evaluation of the impact of Omicron variant of concern sublineage BA.4 and BA.5 on the sensitivity of RT-qPCR assays for SARS-CoV-2 detection using whole genome sequencing.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VoC) Omicron (B.1.1.529) has rapidly spread around the world, presenting a new threat to global public human health. Due to the large number of mutations accumulated by SARS-CoV-2 Omicron, concerns have emerged over potentially reduced diagnostic accuracy of reverse-transcription polymerase chain reaction (RT-qPCR), the gold standard diagnostic test for diagnosing coronavirus disease 2019 (COVID-19). Thus, we aimed to assess the impact of the currently endemic Omicron sublineages BA.4 and BA.5 on the integrity and sensitivity of RT-qPCR assays used for coronavirus disease 2019 (COVID-19) diagnosis via in silico analysis. We employed whole genome sequencing data and evaluated the potential for false negatives or test failure due to mismatches between primers/probes and the Omicron VoC viral genome. METHODS: In silico sensitivity of 12 RT-qPCR tests (containing 30 primers and probe sets) developed for detection of SARS-CoV-2 reported by the World Health Organization (WHO) or available in the literature, was assessed for specifically detecting SARS-CoV-2 Omicron BA.4 and BA.5 sublineages, obtained after removing redundancy from publicly available genomes from National Center for Biotechnology Information (NCBI) and Global Initiative on Sharing Avian Influenza Data (GISAID) databases. Mismatches between amplicon regions of SARS-CoV-2 Omicron VoC and primers and probe sets were evaluated, and clustering analysis of corresponding amplicon sequences was carried out. RESULTS: From the 1164 representative SARS-CoV-2 Omicron VoC BA.4 sublineage genomes analyzed, a substitution in the first five nucleotides (C to T) of the amplicon's 3'-end was observed in all samples resulting in 0% sensitivity for assays HKUnivRdRp/Hel (mismatch in reverse primer) and CoremCharite N (mismatch in both forward and reverse primers). Due to a mismatch in the forward primer's 5'-end (3-nucleotide substitution, GGG to AAC), the sensitivity of the ChinaCDC N assay was at 0.69%. The 10 nucleotide mismatches in the reverse primer resulted in 0.09% sensitivity for Omicron sublineage BA.4 for Thai N assay. Of the 1926 BA.5 sublineage genomes, HKUnivRdRp/Hel assay also had 0% sensitivity. A sensitivity of 3.06% was observed for the ChinaCDC N assay because of a mismatch in the forward primer's 5'-end (3-nucleotide substitution, GGG to AAC). Similarly, due to the 10 nucleotide mismatches in the reverse primer, the Thai N assay's sensitivity was low at 0.21% for sublineage BA.5. Further, eight assays for BA.4 sublineage retained high sensitivity (more than 97%) and 9 assays for BA.5 sublineage retained more than 99% sensitivity. CONCLUSION: We observed four assays (HKUnivRdRp/Hel, ChinaCDC N, Thai N, CoremCharite N) that could potentially result in false negative results for SARS-CoV-2 Omicron VoCs BA.4 and BA.5 sublineages. Interestingly, CoremCharite N had 0% sensitivity for Omicron Voc BA.4 but 99.53% sensitivity for BA.5. In addition, 66.67% of the assays for BA.4 sublineage and 75% of the assays for BA.5 sublineage retained high sensitivity. Further, amplicon clustering and additional substitution analysis along with sensitivity analysis could be used for the modification and development of RT-qPCR assays for detecting SARS-CoV-2 Omicron VoC sublineages.

Solanum nigrum L. in COVID-19 and post-COVID complications: a propitious candidate.

COVID-19 is caused by severe acute respiratory syndrome coronavirus-2, SARS-CoV-2. COVID-19 has changed the world scenario and caused mortality around the globe. Patients who recovered from COVID-19 have shown neurological, psychological, renal, cardiovascular, pulmonary, and hematological complications. In some patients, complications lasted more than 6 months. However, significantly less attention has been given to post-COVID complications. Currently available drugs are used to tackle the complications, but new interventions must address the problem. Phytochemicals from natural sources have been evaluated in recent times to cure or alleviate COVID-19 symptoms. An edible plant, Solanum nigrum, could be therapeutic in treating COVID-19 as the AYUSH ministry of India prescribes it during the pandemic. S. nigrum demonstrates anti-inflammatory, immunomodulatory, and antiviral action to treat the SARS-CoV-2 infection and its post-complications. Different parts of the plant represent a reduction in proinflammatory cytokines and prevent multi-organ failure by protecting various organs (liver, kidney, heart, neuro, and lung). The review proposes the possible role of the plant S. nigrum in managing the symptoms of COVID-19 and its post-COVID complications based on in silico docking and pharmacological studies. Further systematic and experimental studies are required to validate our hypothesis.

Sociodemographic Determinants of Willingness and Extent to Pay for COVID-19 Vaccine in India.

Background: Responding to the fast transmission rates and increasing fatality rates, countries across the world expedited the development and deployment of the vaccine for coronavirus disease 2019 (COVID-19). Evaluation of individuals' willingness to pay (WTP) would provide pertinent information regarding future demand and financing preferences, which shall help to devise the effective payment strategy for COVID-19 vaccination. Methods: A nationwide, cross-sectional, and self-administered online survey using a structured questionnaire was conducted to identify the sociodemographic determinants of willingness and extent to pay for COVID-19 vaccine in India. A non-probability convenience sampling followed by snowball sampling was employed to recruit participants (n = 3,341). The likelihood of sociodemographic determinants to predict willingness and extent to pay was modeled using the multivariate binary logistic regression analysis. Results: Out of 3,371 participants, 68% (n = 2,271) were willingness to pay for COVID-19 vaccine. Results showed significantly higher odds for willingness to pay among participants who were single [adjusted odds ratio (aOR) = 1.394, p < 0.01] and having a family size of 4 members (aOR = 1.346, p < 0.01). The adjusted odds ratio sizably increased from 1.396 for participants whose monthly income was between INR 10,000 and 20,000/month to 2.240 for participants whose monthly income was above INR 50,000/month. Further, out of 2,271 of those participants who were willingness to pay for COVID-19 vaccine, majority (n = 1,246, 54.9%) of participants were willingness to pay below 50% of COVID-19 vaccine cost. This study found that those who are single (aOR = 0.688, p < 0.01), having an income between INR 20,000 and 50,000/month (aOR = 0.686, p < 0.05), and those who belonged to socially disadvantaged category (aOR = 0.450, p < 0.01) were estimated to have significantly lower odds of willingness to pay more than 50% of COVID-19 vaccine cost. Conclusion: This study observed that majority of those participants who willingness to pay for COVID-19 vaccine were willingness to pay only up to 50% of COVID-19 vaccine and income was observed as a precursor predictor of the willingness and extent to pay for COVID-19 vaccine. The understanding on the willingness and extent to pay for COVID-19 vaccine and its sociodemographic determinants will be helpful for making the strategic decisions related to the financing of COVID vaccine in India.

Understanding the mutational frequency in SARS-CoV-2 proteome using structural features.

The prolonged transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in the human population has led to demographic divergence and the emergence of several location-specific clusters of viral strains. Although the effect of mutation(s) on severity and survival of the virus is still unclear, it is evident that certain sites in the viral proteome are more/less prone to mutations. In fact, millions of SARS-CoV-2 sequences collected all over the world have provided us a unique opportunity to understand viral protein mutations and develop novel computational approaches to predict mutational patterns. In this study, we have classified the mutation sites into low and high mutability classes based on viral isolates count containing mutations. The physicochemical features and structural analysis of the SARS-CoV-2 proteins showed that features including residue type, surface accessibility, residue bulkiness, stability and sequence conservation at the mutation site were able to classify the low and high mutability sites. We further developed machine learning models using above-mentioned features, to predict low and high mutability sites at different selection thresholds (ranging 5-30% of topmost and bottommost mutated sites) and observed the improvement in performance as the selection threshold is reduced (prediction accuracy ranging from 65 to 77%). The analysis will be useful for early detection of variants of concern for the SARS-CoV-2, which can also be applied to other existing and emerging viruses for another pandemic prevention.

Ab-CoV: a curated database for binding affinity and neutralization profiles of coronavirus-related antibodies.

SUMMARY: We have developed a database, Ab-CoV, which contains manually curated experimental interaction profiles of 1780 coronavirus-related neutralizing antibodies. It contains more than 3200 datapoints on half maximal inhibitory concentration (IC50), half maximal effective concentration (EC50) and binding affinity (KD). Each data with experimentally known three-dimensional structures are complemented with predicted change in stability and affinity of all possible point mutations of interface residues. Ab-CoV also includes information on epitopes and paratopes, structural features of viral proteins, sequentially similar therapeutic antibodies and Collier de Perles plots. It has the feasibility for structure visualization and options to search, display and download the data. AVAILABILITY AND IMPLEMENTATION: Ab-CoV database is freely available at https://web.iitm.ac.in/bioinfo2/ab-cov/home. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Sociodemographic Determinants of Willingness and Extent to Pay for COVID-19 Vaccine in India

Background Responding to the fast transmission rates and increasing fatality rates, countries across the world expedited the development and deployment of the vaccine for coronavirus disease 2019 (COVID-19). Evaluation of individuals' willingness to pay (WTP) would provide pertinent information regarding future demand and financing preferences, which shall help to devise the effective payment strategy for COVID-19 vaccination. Methods A nationwide, cross-sectional, and self-administered online survey using a structured questionnaire was conducted to identify the sociodemographic determinants of willingness and extent to pay for COVID-19 vaccine in India. A non-probability convenience sampling followed by snowball sampling was employed to recruit participants (n = 3,341). The likelihood of sociodemographic determinants to predict willingness and extent to pay was modeled using the multivariate binary logistic regression analysis. Results Out of 3,371 participants, 68% (n = 2,271) were willingness to pay for COVID-19 vaccine. Results showed significantly higher odds for willingness to pay among participants who were single [adjusted odds ratio (aOR) = 1.394, p < 0.01] and having a family size of 4 members (aOR = 1.346, p < 0.01). The adjusted odds ratio sizably increased from 1.396 for participants whose monthly income was between INR 10,000 and 20,000/month to 2.240 for participants whose monthly income was above INR 50,000/month. Further, out of 2,271 of those participants who were willingness to pay for COVID-19 vaccine, majority (n = 1,246, 54.9%) of participants were willingness to pay below 50% of COVID-19 vaccine cost. This study found that those who are single (aOR = 0.688, p < 0.01), having an income between INR 20,000 and 50,000/month (aOR = 0.686, p < 0.05), and those who belonged to socially disadvantaged category (aOR = 0.450, p < 0.01) were estimated to have significantly lower odds of willingness to pay more than 50% of COVID-19 vaccine cost. Conclusion This study observed that majority of those participants who willingness to pay for COVID-19 vaccine were willingness to pay only up to 50% of COVID-19 vaccine and income was observed as a precursor predictor of the willingness and extent to pay for COVID-19 vaccine. The understanding on the willingness and extent to pay for COVID-19 vaccine and its sociodemographic determinants will be helpful for making the strategic decisions related to the financing of COVID vaccine in India.

Insight into the biological impact of COVID-19 and its vaccines on human health.

COVID-19 (coronavirus disease-2019) is a contagious illness that has been declared a global epidemic by the World Health Organization (WHO). The coronavirus causes diseases ranging in severity from the common cold to severe respiratory diseases and death. Coronavirus primarily affects blood pressure by attaching to the angiotensin converting enzyme 2 (ACE 2) receptor. This virus has an impact on multiple organ systems, including the central nervous system, immune system, cardiovascular system, peripheral nervous system, gastrointestinal tract, endocrine system, urinary system, skin, and pregnancy. For the prevention of COVID-19, various vaccines such as viral-like particle vaccines, entire inactivated virus vaccines, viral vector vaccines, live attenuated virus vaccines, subunit vaccines, RNA vaccines, and DNA vaccines are now available. Some of the COVID-19 vaccines are reported to cause a variety of adverse effects that range from mild to severe in nature. SARS-CoV-2 replication is controlled by the RNA-Dependent RNA-Polymerase enzyme (RdRp). The availability of FDA-approved anti-RdRp drugs (Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir) as potent drugs against SARS-CoV-2 that tightly bind to its RdRp may aid in the treatment of patients and reduce the risk of the mysterious new form of COVID-19 viral infection. RdRp inhibitors, such as remdesivir (an anti-Ebola virus experimental drug) and favipiravir (an anti-influenza drug), inhibit RdRp and thus slow the progression of COVID-19 and associated clinical symptoms, as well as significantly shorten recovery time. Molnupiravir, an orally active RdRp inhibitor and noval broad spectrum antiviral agent, is an isopropyl pro-drug of EIDD-1931 for emergency use. Galidesivir's in vitro and in vivo activities are limited to RNA of human public health concern. Top seeds for antiviral treatments with high potential to combat the SARS-CoV-2 strain include guanosine derivatives (IDX-184), setrobuvir, and YAK. The goal of this review is to compile scattered information on available COVID-19 vaccines and other treatments for protecting the human body from their harmful effects and to provide options for making better choices in a timely manner.

Pediatric Atypical Hemolytic Uremic Syndrome Advances.

Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by dysregulation of the alternate pathway. The diagnosis of aHUS is one of exclusion, which complicates its early detection and corresponding intervention to mitigate its high rate of mortality and associated morbidity. Heterozygous mutations in complement regulatory proteins linked to aHUS are not always phenotypically active, and may require a particular trigger for the disease to manifest. This list of triggers continues to expand as more data is aggregated, particularly centered around COVID-19 and pediatric vaccinations. Novel genetic mutations continue to be identified though advancements in technology as well as greater access to cohorts of interest, as in diacylglycerol kinase epsilon (DGKE). DGKE mutations associated with aHUS are the first non-complement regulatory proteins associated with the disease, drastically changing the established framework. Additional markers that are less understood, but continue to be acknowledged, include the unique autoantibodies to complement factor H and complement factor I which are pathogenic drivers in aHUS. Interventional therapeutics have undergone the most advancements, as pharmacokinetic and pharmacodynamic properties are modified as needed in addition to their as biosimilar counterparts. As data continues to be gathered in this field, future advancements will optimally decrease the mortality and morbidity of this disease in children.

A novel hybrid SEIQR model incorporating the effect of quarantine and lockdown regulations for COVID-19.

Mitigating the devastating effect of COVID-19 is necessary to control the infectivity and mortality rates. Hence, several strategies such as quarantine of exposed and infected individuals and restricting movement through lockdown of geographical regions have been implemented in most countries. On the other hand, standard SEIR based mathematical models have been developed to understand the disease dynamics of COVID-19, and the proper inclusion of these restrictions is the rate-limiting step for the success of these models. In this work, we have developed a hybrid Susceptible-Exposed-Infected-Quarantined-Removed (SEIQR) model to explore the influence of quarantine and lockdown on disease propagation dynamics. The model is multi-compartmental, and it considers everyday variations in lockdown regulations, testing rate and quarantine individuals. Our model predicts a considerable difference in reported and actual recovered and deceased cases in qualitative agreement with recent reports.

Elucidating important structural features for the binding affinity of spike - SARS-CoV-2 neutralizing antibody complexes.

The coronavirus disease 2019 (COVID-19) has affected the lives of millions of people around the world. In an effort to develop therapeutic interventions and control the pandemic, scientists have isolated several neutralizing antibodies against SARS-CoV-2 from the vaccinated and convalescent individuals. These antibodies can be explored further to understand SARS-CoV-2 specific antigen-antibody interactions and biophysical parameters related to binding affinity, which can be utilized to engineer more potent antibodies for current and emerging SARS-CoV-2 variants. In the present study, we have analyzed the interface between spike protein of SARS-CoV-2 and neutralizing antibodies in terms of amino acid residue propensity, pair preference, and atomic interaction energy. We observed that Tyr residues containing contacts are highly preferred and energetically favorable at the interface of spike protein-antibody complexes. We have also developed a regression model to relate the experimental binding affinity for antibodies using structural features, which showed a correlation of 0.93. Moreover, several mutations at the spike protein-antibody interface were identified, which may lead to immune escape (epitope residues) and improved affinity (paratope residues) in current/emerging variants. Overall, the work provides insights into spike protein-antibody interactions, structural parameters related to binding affinity and mutational effects on binding affinity change, which can be helpful to develop better therapeutics against COVID-19.

Exploring antibody repurposing for COVID-19: beyond presumed roles of therapeutic antibodies.

The urgent need for a treatment of COVID-19 has left researchers with limited choice of either developing an effective vaccine or identifying approved/investigational drugs developed for other medical conditions for potential repurposing, thus bypassing long clinical trials. In this work, we compared the sequences of experimentally verified SARS-CoV-2 neutralizing antibodies and sequentially/structurally similar commercialized therapeutic monoclonal antibodies. We have identified three therapeutic antibodies, Tremelimumab, Ipilimumab and Afasevikumab. Interestingly, these antibodies target CTLA4 and IL17A, levels of which have been shown to be elevated during severe SARS-CoV-2 infection. The candidate antibodies were evaluated further for epitope restriction, interaction energy and interaction surface to gauge their repurposability to tackle SARS-CoV-2 infection. Our work provides candidate antibody scaffolds with dual activities of plausible viral neutralization and immunosuppression. Further, these candidate antibodies can also be explored in diagnostic test kits for SARS-CoV-2 infection. We opine that this in silico workflow to screen and analyze antibodies for repurposing would have widespread applications.

Traditional plants as immunobooster - preventive strategy against COVID-19

Today India is fighting against an infectious disease called coronavirus. Elderly populations with non-communicable diseases like diabetes, hypertension, cardiovascular disease, respiratory diseases are more affected by coronavirus because of lack of immunity. The objective of the present review was to study herbs and spices as preventive strategy by enhancing the immune system of human body. About 100 research papers were studied from various databases like Pubmed, Google Scholar, web of Science, Scopus, Science Direct etc. both national and global research papers were included. Most of the database included for consist of original research papers and systematic review papers. The data was collected for spices- garlic, ginger, cinnamon, turmeric and herbs - giloy, ashwagandha, white musli and tulsi. The data revealed that all their herbs and spices have a positive effect on immune system. They have been recognized as sources of various phytochemicals and antioxidants that defense against oxidative stress and enhance immunity. They also possess anti-tumour effects by inhibiting transformation, tumour - initiation, tumour- promotion, invasion, angiogenesis, and find stage of metastasis. A positive effect was observed on lymphocyte and macrophages. The present review concluded that consumption of these herbs and spices can act as a preventive strategy against infection and COVID 19.

Safer Practice of Aesthetic Dermatology during the COVID-19 Pandemic: Recommendations by SIG Aesthetics (IADVL Academy).

The COVID-19 pandemic caused by the SARS-CoV-2 virus, has changed the homeostasis of the medical world. In this critical phase, in addition to the general recommendations issued by World Health Organization (WHO) for medical practitioners and health care givers, certain other precautions and safe care practices need to be emphasized which are unique to each branch of medicine. Aesthetic dermatology is no exception. With aesthetic treatments on the rise, it is pertinent to formulate safe practices for aesthetic dermatology to protect the doctor, health staff and the patients from getting exposed during this phase and in the aftermath of the pandemic. Recommendations for surgical and dental procedures advice to defer such procedures. This can be extrapolated to aesthetic dermatology also, but once health care services start, there should be some safety recommendations to be followed until we have definitive management or a vaccine for it.