key: cord-0849792-48xwfr9i authors: Abdullah, Abdullah; Faisal, Shah; Aman, Komal; Rahman, Anees ur title: Innate Immune-mediated Antiviral Response to SARS-CoV-2 and Convalescent sera a potential Prophylactic and Therapeutic Agent to Tackle COVID-19 date: 2020-08-16 journal: Antib Ther DOI: 10.1093/abt/tbaa019 sha: 4c2d92481c1e7ca2ac075f9caef4b945bb0a032f doc_id: 849792 cord_uid: 48xwfr9i The whole world is confronting the pandemic of SARS-CoV-2. Unfortunately there is no vaccine to prevent from novel coronavirus infection. Beside several experimental drugs, the strong immune responses and convalescent sera are the current two potential options to tackle COVID-19 infection. Innate immune-mediated antiviral responses is initiated by the recognition of viral invasion through PAMPs. In coronavirus the pathogen associated molecular patterns are recognized by toll like receptors (TLR-3 & 7), endosomal ribonucleic acid receptors, RNA in cytosol and by pattern recognition receptor (PRR RIG-1) in the alveolar cells and site of invasion. Nuclear factor (NF-κB) and interferon regulatory transcription factor (IRF3) are activated in response to above recognition episode and translocate to nucleus. These transcription factors in the nucleus initiate the expression of interferon type 1 and pro-inflammatory cytokine storm, which leads to first line of defense at the site of viral entrance. The effectiveness of innate immune system is greatly relies on type 1 interferons and its cascade, because of their role in inhibition of viral replication and initiation of adaptive immune responses. The successful interferon type 1 response put down the viral replication and transmission at prompt point. Passive immunization is the administering of antibodies into infected patients which is taken from recovered individuals. The convalescent sera of the recovered COVID-19 patients are containing antiviral neutralizing antibodies and is used therapeutically for infected individuals by SARS-CoV-2 and for the purpose of prophylaxis in exposed individuals. The convalescent sera is found effective when administered early at the onset of symptoms. As of December 2019, human population is facing pandemic of SARS-CoV-2, which is responsible for causing coronavirus infection, named as COVID-19. SARS-CoV-2 affect billions of people and still spreading rapidly throughout the world. Though the mortality of COVID-19 is far lower than SARS-CoV and MERS but the transmission rate is very high (1) . The deaths and confirmed cases are increasing day by day (2) . Currently there are no specific vaccine, monoclonal antibody, and drugs for treatment, as this virus seems to be novel (3) . Vaccines for COVID-19 are in rapid developing stage and will be available soon (4) . The innate immune responses has a key role in slowing down the viral replication, the innate immune responses are stronger in young population than aged population. Therefore the mortality rate of SARS-CoV-2 is higher in old age population than adult. The current situation proclaim that passive immunization or passive antibody therapy is the best option for treatment and prevention of their immunoglobulin containing sera immediately (4, 5) . The current article focused on how innate immune responses and convalescent sera get to grip with SARS-CoV-2. The current article also addresses associated risks and benefits with the use of convalescent sera, immunopathology and immune evasion mechanism of COVID-19. The COVID-19 initial site of infection and pathogenesis is still under investigation however, in most cases the lungs might be affected. Person to person transmission by droplets, cough, sneeze, talk, and close contact is prime mode of transmission. The incubation period is 2-14 days (6), and the rapid reproduction rate is 2.2-2.6 (7). 80% of the cases are asymptomatic or showing mild symptoms, while 20% cases are critical, which means that fatality and severity of SARS-CoV-2 is less than MERS and SARS, however the SARS-CoV-2 presents similar symptoms with SARS and MERS such as fever and respiratory symptoms. The percentage of gastrointestinal symptoms such as diarrhea in MERS and SARS is 20-25%, but in COVID-19 these symptoms are rare (8) . Mostly COVID-19 infected patients develops lymphopenia along with pneumonia (9). IL-2, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP-1A, and TNFα were also reported in severe infected patients of COVID-19 (9) . These pro-inflammatory cytokine storm, may initiate viral sepsis and inflammatory-induced lung injury. Which results in acute respiratory distress syndrome, pneumonitis, respiratory failure, shock, multiple organ failure and eventually death. The mortality rate of SARS-CoV-2 is 2.4% (9) , this mortality rate is due to organ failure in aged peoples having past complications of hypertension, diabetes and cardiopulmonary problems. The coronavirus have longer incubation period of 2-14 days as compared to influenza, which is 1-4 days (10), it is due to the reason that coronaviruses dampen the immune responses and adapt to evade the immune barrier. Most evasion mechanisms involves the inhibition of interferon type 1 protiens. The M protein of coronavirus has a key role in immune modulation. Analysis of two MERS cases revealed that infected patients has low titer of type 1 interferons, while the recovered individuals have high titer of type 1 interferons (11) . When the dendritic cells and macrophages get infected by coronavirus, it leads to the down regulation of antigen presentation via MHC class I and II and stop or diminish the activation of T-cells, thus there will be no adaptive immunity to the virus (12). Innate immune responses of host is the by birth immunity, which present first barrier to any kind of pathogen. Although there are limited information on the innate immune responses to COVID-19, but increase in neutrophils (38%), reduction in lymphocytes (35%), increased serum interleukin-6 (52%) and increased C-reactive protein (84%) were also investigated in a study in Administration of antibodies to the susceptible individuals to a disease, for the purpose of prevention and treatment is called passive antibody therapy and the process is called passive immunization. In active immunization or vaccination the triggering of immune responses to develop took much time and differ according to the recipient. Thus the immediate way to prevent the susceptible population is passive antibody therapy. In 1890s foregoing to the happening of antimicrobial therapy in 1940s, the Passive immunization was considered the sole mean of handling defined infectious diseases (19, 20) . In case of SARS-CoV it found that the convalescent sera contains nAbs to the concern virus (21). The mechanism of action is same for SARS-CoV-2, the passive immunization initiate protection by viral neutralization. However, Abdependent cellular cytotoxicity and phagocytosis pathways are also to be considered. For SARS-CoV-2 the possible source of antibodies are human convalescent sera or to generate it in animal host, just like genetically engineered cow that produces human Abs (22) . The only immediate available antibody is human convalescent sera, however many preparatory methods will be available soon (Figure 2) . The number of likely and potential donors is directly proportional to the number of recovered individuals. The effectiveness of passive antibodies is more for prophylaxis than for disease treatment. The antibody therapy is efficient when injected just after appearance of signs and symptoms. The causes for temporary differences in effectiveness is not known properly but passive immunization works by viral neutralization (23), the antibody also works by modification of initial inflammatory responses (24) . The passive antibody therapy was found effective for pneumococcal pneumonia, when administered immediately just after the appearance of signs and symptoms, the antibody is found non-effective when administered after three days of onset of symptoms (25) . The effectiveness of antibody also depends on its amount to be administered. The administered antibody circulates in the blood of susceptible person and when reach tissues it initiates protection against infection. The duration of affectivity can last from weeks to months depending on the antibody composition and quantity. (37) outbreaks. Although there are differences in every viral disease and epidemic, the important historical approaches give evidences and will be useful to protect population that is confronting COVID-19 pandemic. There have been two epidemics in the 21 st century the SARS-CoV-1 and MERS. The SARS epidemic is continued but the MERS is endemic now. Due to the mortality and unavailability of vaccine leads to the use of convalescent sera in both outbreaks. In SARS-CoV-1 epidemic the largest study was held in Hong Kong in which 80 patients were treated with convalescent sera before day 14 and discharged from hospital before day 22 with improved prognosis, it revealed that the early administration of convalescent sera is more effective than later (38) . Three SARS-CoV-1 infected patients were treated with 500ml of convalescent sera, the reduction in viral titer and mortality were recorded (39) . Three MERS infected patients were also treated with Convalescent or Passive antibody therapy, two of them produce nAbs and remaining one not (40) , this study highlights the limitation in using of convalescent sera it means that the recovered individual may not have enough titer of nAbs (41) . In continuance with the above point, in a study neutralizing antibodies were found in 87 cases out of 99 with a geometric mean titer of 1:61 that were analyzed for presence of neutralizing antibodies (21) . This study suggests that some patients produce high-titer responses or antibody decline with time. Possibility is there for the production of non-nAbs (42) (43) (44) . In china convalescent sera was used for the treatment of COVID-19 (45) . In other countries trails are started on convalescent sera. The available information on the use of convalescent sera or passive immunization for the treatment of SARS-CoV-2 suggests that early administration of convalescent serum reduces viral abundance and was found safe. Some conditions are required for the deployment of passive immunization which are the The convalescent serum from COVID-19 recovered individuals can be either used for prophylaxis or for the treatment of disease. Benefits in prophylaxis, the administration of responses is another theoretical risk, antibody administration to SARS-CoV-2 exposed individuals to prevent disease, and it leads such individuals susceptible to reinfection. Passive antibody administration prior to vaccination with RSV was reported to attenuate antibody mediated or humoral immunity rather than cellular or cell mediated immunity (48) . It could be investigated by assessment of immune responses of SARS-CoV-2 exposed individuals and 12 convalescent sera treated individuals in clinical trials. If the risk exits, the patients could be immunized against COVID-19 as the vaccine get at hand. Historical experiences and current available information suggests that passive immunization is safe for COVID-19 patients at higher risk and elderly people with chronic diseases. However, for all cases convalescent serum therapy and its administration is considered a risk-benefit assessment.  The innate immune-mediated antiviral responses against coronavirus greatly relies on downstream cascade mechanisms of type 1 interferon, increase and decrease in total blood neutrophils and lymphocytes.  The fatality is also associated with chronic diseases. Historical precedents and former experiences with the use of convalescent sera proved its prophylactic and therapeutic efficacy. The convalescent sera is more effective when administered just after the onset of symptoms.  The neutralizing antibody titer must be higher to cope with the virus. The convalescent sera is the safe and proved way to tackle SARS-CoV-2. However large number of recovered patients and expertise are required.  Local and federal government are advised to start immediate trails on this type of treatment because we have no vaccine yet. A Perspective Study on Oral-fecal Transmission of COVID-19, Its Prevention and Management Coronavirus update (live) The Pandemic of Novel Coronavirus Disease 2019 (COVID-19): Need for an Immediate Action Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding Center for Disease Control and Prevention Symptoms of Novel Coronavirus A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster Clinical features of patients infected with 2019 novel coronavirus in Wuhan Incubation periods of acute respiratory viral infections: a systematic review Distinct immune response in two MERS-CoV-infected patients: can we go from bench to bedside? Modulation of the immune response by Middle East respiratory syndrome coronavirus The convalescent sera option for containing COVID-19. The Journal of clinical investigation A pneumonia outbreak associated with a new coronavirus of probable bat origin A new coronavirus associated with human respiratory disease in China Clinical features of patients infected with 2019 novel coronavirus in Wuhan A Novel Coronavirus from Patients with Pneumonia in China SARS and MERS: recent insights into emerging coronaviruses Return to the past: the case for antibody-based therapies in infectious diseases Passive antibody therapy for infectious diseases A serological survey on neutralizing antibody titer of SARS convalescent sera Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study Perspective: hypothesis: serum IgG antibody is sufficient to confer protection against infectious diseases by inactivating the inoculum Antibody-mediated regulation of cellular immunity and the inflammatory response Serum therapy revisted: animal models of infection and development of passive antibody therapy The prophylactic use of measles convalescent serum Use of convalescent measles serum to control measles in a preparatory school Therapeutic use of antipoliomyelitits serum in preparalytic cases of poliomyelitis Hark back: passive immunotherapy for influenza and other serious infections Mumps; use of convalescent serum in the treatment and prophylaxis of orchitis Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection Evaluation of convalescent whole blood for treating Ebola virus disease in Freetown The Use of TKM-100802 and convalescent plasma in 2 patients with Ebola virus disease in the United States Successful treatment of avian influenza with convalescent plasma Treatment with convalescent plasma for influenza A (H5N1) infection Successful treatment of avian-origin influenza A (H7N9) infection using convalescent plasma Use of convalescent plasma therapy in SARS patients in Hong Kong Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital Challenges of convalescent plasma infusion therapy in Middle East respiratory coronavirus infection: a single centre experience Feasibility of using convalescent plasma immunotherapy for MERS-CoV infection, Saudi Arabia Fc-mediated antibody effector functions during respiratory syncytial virus infection and disease The roles of host and viral antibody fc receptors in herpes simplex virus (HSV) and human cytomegalovirus (HCMV) infections and immunity A role for Fc function in therapeutic monoclonal antibody-mediated protection against ebola virus China puts 245 COVID-19 patients on convalescent plasma therapy. News release. Xinhua Molecular mechanism for antibody-dependent enhancement of coronavirus entry The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis Passively acquired antibodies suppress humoral but not cell-mediated immunity in mice immunized with live attenuated respiratory syncytial virus vaccines COVID-19: Review of Epidemiology and Potential Treatments Against We are grateful to Department of Microbiology, Abdul Wali Khan University, Mardan, KPK, Pakistan for providing assistance and guideline.Funding source and financial assistance are not applicable for this study. Authors declare no conflict of interest.