Dengue & COVID-19: A Comparison and the Challenges at Hand.

The COVID-19 pandemic caused by SARS-CoV-2 spread across many countries between 2020 and 2022. The similarities in clinical presentation with other endemic diseases pose a challenge to physicians in effectively diagnosing and treating the infection. Approximately 129 nations have a risk of dengue infection, and more than 100 of those are endemic to dengue. During the COVID-19 pandemic, the number of dengue cases decreased in many countries owing to the isolation measures followed. However, the common clinical presentation between them has led to misdiagnosis. Both COVID-19 and dengue fever cause a surge in pro-inflammatory cytokines and chemokines, thus sharing a common pathophysiology. False positive serological test results also posed difficulty differentiating between COVID-19 and dengue fever. This review aims to compare the clinical features, pathophysiology, and immune response between dengue and COVID-19, to benefit public health management during the pandemic.

Evolving understanding of antibody-dependent enhancement (ADE) of SARS-CoV-2.

Since immune system and internal environment in vivo are large and complex, the interpretation of the observed immune effect from the perspective of a single immune cell or antibody seems a little feeble. Many studies have shown that specific antibodies against " former" viruses have a reduced ability to neutralize "new" mutant strains. However, there is no comprehensive and clear view of whether there will be Antibody-dependent enhancement (ADE). We review the latest relevant studies, hoping to explain the ADE of SARS-CoV-2 infection sometimes observed in some patients.

Dengue Infection - Recent Advances in Disease Pathogenesis in the Era of COVID-19.

The dynamics of host-virus interactions, and impairment of the host's immune surveillance by dengue virus (DENV) serotypes largely remain ambiguous. Several experimental and preclinical studies have demonstrated how the virus brings about severe disease by activating immune cells and other key elements of the inflammatory cascade. Plasmablasts are activated during primary and secondary infections, and play a determinative role in severe dengue. The cross-reactivity of DENV immune responses with other flaviviruses can have implications both for cross-protection and severity of disease. The consequences of a cross-reactivity between DENV and anti-SARS-CoV-2 responses are highly relevant in endemic areas. Here, we review the latest progress in the understanding of dengue immunopathogenesis and provide suggestions to the development of target strategies against dengue.

Clinical aspects and presumed etiology of multisystem inflammatory syndrome in children (MIS-C): A review.

The COVID-19 outbreak sparked by SARS-CoV-2, begat significant rates of malady worldwide, where children with an abnormal post-COVID ailment called the Multisystem Inflammatory Syndrome (MIS-C), were reported by April 2020. Here we have reviewed the clinical characteristics of the pediatric patients and the prognosis currently being utilized. A vivid comparison of MIS-C with other clinical conditions has been done. We have addressed the probable etiology and fundamental machinery of the inflammatory reactions, which drive organ failure. The involvement of androgen receptors portrays the likelihood of asymptomatic illness in children below adolescence, contributing to the concept of antibody-dependent enhancement.

Adverse effects of vaccinations and potential therapies against COVID-19

Publication indicates that antiviral therapies are definitely more harmful and less effective as well as less accessible than vaccinations. Antiviral therapies are generally not effective in phase II and III of the disease. The use of antiviral therapies in all patients would doom them to many side effects, and only 10% of patients go from phase I to phase II and require such treatment. The chance of curing COVID-19 patients in phase II and III of the disease is rapidly declining. Vaccinations, on the other hand, are very effective. Confirmed AEFI are rare and intensive research is underway to elucidate their etiopathogenesis. From a biotechnological point of view, vaccination leads to the production of CAR-T-like immunotherapy or monoclonal antibodies, that work from the 1st day of infection, not from the first day of symptom onset, when patients can start some pharmacological therapy. In the case of COVID-19, a clear advantage of vaccination over pharmacological therapy has emerged. Nevertheless, because vaccination may not be effective for all patients, working on therapy should also be intensively carried out. Proper pharmacotherapy administration depends on the quick cooperation of diagnosticians with doctors. It also depends on the development of tests to select therapies and determine in whom a disease such as COVID-19 will change from phase I to phase II. Vaccinated patients will probably respond better to treatments.

Antibody-dependent enhancement of virus infection and disease: implications in COVID-19.

Antibody-dependent enhancement (ADE) can be seen in a variety of viruses. It has a deleterious impact on antibody treatment of viral infection. This effect was first discovered in the dengue virus, and it has since been discovered in the coronavirus. Over 213 million people have been affected by the rapid spread of the newly emerging coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19). The new coronavirus offers a significant threat and has sparked widespread concern. ADE in dengue virus and other viruses are discussed with possible effect on COVID-19 treatment and vaccine development will need to consider this phenomenon to ensure it is mitigated and avoided altogether. In these case scenarios, the role of ADE and its clinical consequences remains to be explored for this newly detected virus.

One dose of COVID-19 nanoparticle vaccine REVC-128 protects against SARS-CoV-2 challenge at two weeks post-immunization.

ABSTRACTA COVID-19 vaccine that can give early protection is needed to eliminate the viral spread efficiently. Here, we demonstrate the development of a nanoparticle vaccine candidate, REVC-128, in which multiple trimeric spike ectodomains with glycine (G) at position 614 were multimerized onto a nanoparticle. In-vitro characterization of this vaccine confirms its structural and antigenic integrity. In-vivo immunogenicity evaluation in mice indicates that a single dose of this vaccine induces potent serum neutralizing antibody titre at two weeks post-immunization. This is significantly higher than titre caused by trimeric spike protein without nanoparticle presentation. The comparison of serum binding to spike subunits between animals immunized by a spike with and without nanoparticle presentation indicates that nanoparticle prefers the display of spike RBD (Receptor-Binding Domain) over S2 subunit, likely resulting in a more neutralizing but less cross-reactive antibody response. Moreover, a Syrian golden hamster in-vivo model for the SARS-CoV-2 virus challenge was implemented two weeks post a single dose of REVC-128 immunization. The results showed that vaccination protects hamsters against the SARS-CoV-2 virus challenge with evidence of steady body weight, suppressed viral loads and alleviation of tissue damage for protected animals, compared with ∼10% weight loss, high viral loads and tissue damage in unprotected animals. Furthermore, the data showed that vaccine REVC-128 is thermostable at up to 37°C for at least 4 weeks. These findings, along with a history of safety for protein vaccines, suggest that the REVC-128 is a safe, stable and efficacious single-shot vaccine to give the earliest protection against SARS-CoV-2 infection.

Characterization of MW06, a human monoclonal antibody with cross-neutralization activity against both SARS-CoV-2 and SARS-CoV.

The global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in widespread social and economic disruption. Effective interventions are urgently needed for the prevention and treatment of COVID-19. Neutralizing monoclonal antibodies (mAbs) have demonstrated their prophylactic and therapeutic efficacy against SARS-CoV-2, and several have been granted authorization for emergency use. Here, we discover and characterize a fully human cross-reactive mAb, MW06, which binds to both SARS-CoV-2 and SARS-CoV spike receptor-binding domain (RBD) and disrupts their interaction with angiotensin-converting enzyme 2 (ACE2) receptors. Potential neutralization activity of MW06 was observed against both SARS-CoV-2 and SARS-CoV in different assays. The complex structure determination and epitope alignment of SARS-CoV-2 RBD/MW06 revealed that the epitope recognized by MW06 is highly conserved among SARS-related coronavirus strains, indicating the potential broad neutralization activity of MW06. In in vitro assays, no antibody-dependent enhancement (ADE) of SARS-CoV-2 infection was observed for MW06. In addition, MW06 recognizes a different epitope from MW05, which shows high neutralization activity and has been in a Phase 2 clinical trial, supporting the development of the cocktail of MW05 and MW06 to prevent against future escaping variants. MW06 alone and the cocktail show good effects in preventing escape mutations, including a series of variants of concern, B.1.1.7, P.1, B.1.351, and B.1.617.1. These findings suggest that MW06 recognizes a conserved epitope on SARS-CoV-2, which provides insights for the development of a universal antibody-based therapy against SARS-related coronavirus and emerging variant strains, and may be an effective anti-SARS-CoV-2 agent.

Antibody Response against SARS-CoV-2 and Seasonal Coronaviruses in Nonhospitalized COVID-19 Patients.

The majority of infections with SARS-CoV-2 are asymptomatic or mild without the necessity of hospitalization. It is of importance to reveal if these patients develop an antibody response against SARS-CoV-2 and to define which antibodies confer virus neutralization. We conducted a comprehensive serological survey of 49 patients with a mild course of disease and quantified neutralizing antibody responses against a clinical SARS-CoV-2 isolate employing human cells as targets. Four patients (8%), even though symptomatic, did not develop antibodies against SARS-CoV-2, and two other patients (4%) were positive in only one of the six serological assays employed. For the remaining 88%, antibody response against the S protein correlated with serum neutralization whereas antibodies against the nucleocapsid were poor predictors of virus neutralization. None of the sera enhanced infection of human cells with SARS-CoV-2 at any dilution, arguing against antibody-dependent enhancement of infection in our system. Regarding neutralization, only six patients (12%) could be classified as high neutralizers. Furthermore, sera from several individuals with fairly high antibody levels had only poor neutralizing activity. In addition, employing a novel serological Western blot system to characterize antibody responses against seasonal coronaviruses, we found that antibodies against the seasonal coronavirus 229E might contribute to SARS-CoV-2 neutralization. Altogether, we show that there is a wide breadth of antibody responses against SARS-CoV-2 in patients that differentially correlate with virus neutralization. This highlights the difficulty to define reliable surrogate markers for immunity against SARS-CoV-2.IMPORTANCE There is strong interest in the nature of the neutralizing antibody response against SARS-CoV-2 in infected individuals. For vaccine development, it is especially important which antibodies confer protection against SARS-CoV-2, if there is a phenomenon called antibody-dependent enhancement (ADE) of infection, and if there is cross-protection by antibodies directed against seasonal coronaviruses. We addressed these questions and found in accordance with other studies that neutralization is mediated mainly by antibodies directed against the spike protein of SARS-CoV-2 in general and the receptor binding site in particular. In our test system, utilizing human cells for infection experiments, we did not detect ADE. However, using a novel diagnostic test we found that antibodies against the coronavirus 229E might be involved in cross-protection to SARS-CoV-2.

COVID-19 Vaccines: Should We Fear ADE?

Might COVID-19 vaccines sensitize humans to antibody-dependent enhanced (ADE) breakthrough infections? This is unlikely because coronavirus diseases in humans lack the clinical, epidemiological, biological, or pathological attributes of ADE disease exemplified by dengue viruses (DENV). In contrast to DENV, SARS and MERS CoVs predominantly infect respiratory epithelium, not macrophages. Severe disease centers on older persons with preexisting conditions and not infants or individuals with previous coronavirus infections. Live virus challenge of animals given SARS or MERS vaccines resulted in vaccine hypersensitivity reactions (VAH), similar to those in humans given inactivated measles or respiratory syncytial virus vaccines. Safe and effective COVID-19 vaccines must avoid VAH.

Emergence of ancient convalescent plasma (CP) therapy: To manage COVID-19 pandemic.

Since December 2019, the human populations of the 195 global countries continue experiencing grave health and life threats due to the current COVID-19 pandemic. As a result of the novelty of the pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), at present there is lack of preventive as well as therapeutic options for treating and managing the infection. The use of ancient immunotherapeutic technique - the convalescent plasma (CP) therapy, may act as an immediate and available option to control the COVID-19 pandemic. This review provides a concept and understanding on the CP therapy, its potential to control SARS-CoV-2 pandemic. The CP therapy might act as an immediate saviour for society from the virus. Although the CP therapy has exert affirmative result against COVID-19 it has not been recommended for long time use in COVID-19 and this review gives support for its possible application.

Progress and Pitfalls in the Quest for Effective SARS-CoV-2 (COVID-19) Vaccines.

There are currently around 200 SARS-CoV-2 candidate vaccines in preclinical and clinical trials throughout the world. The various candidates employ a range of vaccine strategies including some novel approaches. Currently, the goal is to prove that they are safe and immunogenic in humans (phase 1/2 studies) with several now advancing into phase 2 and 3 trials to demonstrate efficacy and gather comprehensive data on safety. It is highly likely that many vaccines will be shown to stimulate antibody and T cell responses in healthy individuals and have an acceptable safety profile, but the key will be to confirm that they protect against COVID-19. There is much hope that SARS-CoV-2 vaccines will be rolled out to the entire world to contain the pandemic and avert its most damaging impacts. However, in all likelihood this will initially require a targeted approach toward key vulnerable groups. Collaborative efforts are underway to ensure manufacturing can occur at the unprecedented scale and speed required to immunize billions of people. Ensuring deployment also occurs equitably across the globe will be critical. Careful evaluation and ongoing surveillance for safety will be required to address theoretical concerns regarding immune enhancement seen in previous contexts. Herein, we review the current knowledge about the immune response to this novel virus as it pertains to the design of effective and safe SARS-CoV-2 vaccines and the range of novel and established approaches to vaccine development being taken. We provide details of some of the frontrunner vaccines and discuss potential issues including adverse effects, scale-up and delivery.

The 2020 Pandemic: Current SARS-CoV-2 Vaccine Development.

Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome infecting animals and humans. Coronaviruses have been described more than 70 years ago and contain many species. Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) are lethal species caused by human coronaviruses (HCoVs). Currently, a novel strain of HCoVs, named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (Covid-19). SARS-CoV-2 was first identified in December 2019 in Wuhan, the capital city of the Hubei province of China, and has since spread worldwide causing an outbreak in more than 200 countries. The SARS-CoV-2 outbreak was declared a pandemic on March 11th, 2020 and a public health emergency of international concern (PHEIC) in late January 2020 by the World Health Organization (WHO). SARS-CoV-2 infects the respiratory tract causing flu-like symptoms and, in some, may cause severe illness like pneumonia and multi-organ failure leading to death. Today, Covid-19 cases almost reaching 9 million, with more than 450 thousand deaths. There is an urgent demand for developing a vaccine since no effective therapies or vaccines have been approved to this day to prevent or minimize the spread of the infection. In this review, we summarized the furthest vaccines in the clinical pipeline.

Antibody-dependent enhancement of coronavirus.

Antibody-dependent enhancement (ADE) exists in several kinds of virus. It has a negative influence on antibody therapy for viral infection. This effect was first identified in dengue virus and has since also been described for coronavirus. To date, the rapid spread of the newly emerged coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), has affected over 3.8 million people across the globe. The novel coronavirus poses a great challenge and has caused a wave of panic. In this review, antibody-dependent enhancements in dengue virus and two kinds of coronavirus are summarized. Possible solutions for the effects are reported. We also speculate that ADE may exist in SARS-CoV-2.

Antibody Dependent Enhancement Due to Original Antigenic Sin and the Development of SARS.

Human coronavirus (HCoV) is one of the most common causes of respiratory tract infections throughout the world. Two phenomena observed so far in the development of the SARS-CoV-2 pandemic deserve further attention. First, the relative absence of clinical signs of infections in children, second, the early appearance of IgG in certain patients. From the point of view of immune system physiology, such an early rise of specific IgG is expected in secondary immune responses when memory to a cross-reactive antigen is present, usually from an earlier infection with a coronavirus. It is actually typical for the immune system to respond, to what it already knows, a phenomenon that has been observed in many infections with closely related viruses and has been termed "original antigenic sin." The question then arises whether such cross-reactive antibodies are protective or not against the new virus. The worst scenario would be when such cross-reactive memory antibodies to related coronaviruses would not only be non-protective but even enhance infection and the clinical course. Such a phenomenon of antibody dependent enhancement (ADE) has already been described in several viral infections. Thus, the development of IgG against SARS-CoV-2 in the course of COVID-19 might not be a simple sign of viral clearance and developing protection against the virus. On the contrary, due to cross-reaction to related coronavirus strains from earlier infections, in certain patients IgG might enhance clinical progression due to ADE. The patient's viral history of coronavirus infection might be crucial to the development of the current infection with SARS-CoV-2. Furthermore, it poses a note of caution when treating COVID-19 patients with convalescent sera.

Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools.

Currently there is no effective antiviral therapy for SARS-CoV-2 infection, which frequently leads to fatal inflammatory responses and acute lung injury. Here, we discuss the various mechanisms of SARS-CoV-mediated inflammation. We also assume that SARS-CoV-2 likely shares similar inflammatory responses. Potential therapeutic tools to reduce SARS-CoV-2-induced inflammatory responses include various methods to block FcR activation. In the absence of a proven clinical FcR blocker, the use of intravenous immunoglobulin to block FcR activation may be a viable option for the urgent treatment of pulmonary inflammation to prevent severe lung injury. Such treatment may also be combined with systemic anti-inflammatory drugs or corticosteroids. However, these strategies, as proposed here, remain to be clinically tested for effectiveness.