Humanity is braving a pandemic in the Severe Acute RespiratorySyndrome Coronavirus Virus (SARS-COV-2). Coronavirus disease abbreviated as COVID-19is caused by SARS-COV-2 virus, in layman’s terms, infecting/affecting lungs inmajority of the cases, intestines, liver and kidneys at lower frequency. TheSAR-COV2 infection is apparently (physiologically) characterized with theonset, as well as the severity of symptoms often confused with “flu” likeconditions at the beginning. Based on the spectrum and severity of symptoms,patients are likely to be roughly registered as “Non-severe” and “Severe”patients. SARS-COV-2 virus presents withmultiple symptoms, arguably begins with sore throat, dry cough, fatigue (bodyache) low-grade fever often advancing tohigh grade with the manifestation of breathlessness/difficulty in breathing(dyspnea), and malaise. In most of the cases, transitioning of low fever tohigh fever is taken as an indicative for severity of symptoms and thereforedisease progression. From pathological perspective, Global data on COVID19exerts us into believing the existence of collinearity between setting in ofhigh fever, cytokine storm and lung fibrosis, leading to critically impairedrespiratory function.
COVID-19, as per World Health Organization (WHO) data hasaffected about 465,915 cases as on date while framing this article, with 21,031confirmed deaths and as many as 200 countries affected. Mortality due toCOVID-19, entirely representing the “Severe patient” cohort is mostly due to Respiratory failure, notlimited to but in majority of patients, showing a prevalence in underlying diseases(in the order of most to least) like Hypertension, COPD, Diabetes andcardiovascular disease. Though the mortality rate among “severe/criticalpatient” cohort varies across the countries depending on the age and severityof comorbidity. The rough figures coming across the world indicate that onaverage 80 out of 100 patients are”non-severe” and all of them survive. Remaining 20 categorized as “severepatients” stay critical for longer period out of which 15-17 over recover andshow no signs of disease relapse (with the exception of disease recurring beingreported in few unsolicited cases). Thispiece of information is important to eliminate the perception that every agedpatient with comorbidity expires due to COVID19. Currently, there are no medicinesor vaccines available to treat this disease and the treatment options have beenlimited to the use of other broad specific antiviral drugs alone or incombination with “experimental therapeutic drugs”. In this article, we willemphasis over the suitability of “Convalescent Plasma/Sera” treatment modalityin a given situation.
Passive antibody therapy: A new perspective with old roots.
Antibodies are protein molecules generated in the body byspecialized immune cells in response to an infection. The structure of uniquelyplaced regions in the antibody potentiates the efficacy of certain antibodies(in the pool of antibodies) toneutralize the pathogen (causing infection). Following the infection withSARS-COV-2, our body mounts an immune response, subsequent engagement of immunecells that generate specific antibodies directed to neutralize the virus. Taking a lead based onthis capacitative anti-viral response displayed by our immune system,scientists were able to refine this approach and present it in the form ofpassive antibody therapy. Passive antibody therapy involves administration ofneutralizing antibodies isolated from aperson who has survived the infection into another person who is susceptible orsuffering from infection. This approach is essentially considered as a preventionstrategy rather than the efficacious treatment in itself, for any givendisease. Though it delivers considerable benefits as a treatment modality, alsoin terms of symptom relief and mortality. This approach is in contrast to theactive vaccination wherein the part of genetic material or inactive/attenuatedform of the infectious agent is administered so as to generate an immuneresponse directed against the original pathogen. The process that helps inidentifying the potential vaccine for newly emerging infection and to scale upthe production for making the vaccine globally available, takes lot of time andefforts and often relayed into the market to prevent the relapse or recurringof supposed epidemic. For the 1st phase of emerging infection passive antibodyadministration is the only means of providing immediate immunity and thereforeunbiased treatment to susceptible individuals.
Passive antibody therapy has been in practice historicallyto treat multiple diseases like poliomyelitis, measles, mumps and influenzawhen antimicrobial therapy in the form of antibiotics, anti-virals and vaccines were not available. Taking a case ofCOVID-19, “passive antibody/convalescent plasma” approach would involveadministering serum from COVID-19 survivors into susceptible individual in aneffort to neutralize the virus that may infect (or may have already infected)the individual and providing the person with passive form of immunity.
Experience from prior outbreaks of other coronavirus likeSARS-COV-1, show that sera from the infected patients contain high titers ofneutralizing antibodies to the virus and can be used in a convalescentapproach. Convalescent sera have been used recently with other Coronavirusesduring SARS 1 (2003) and MERS (2012) epidemic in the absence of other effectivetherapies. In one of the largest studies in Hong Kong, patients treated earlywith convalescent sera had better prognosis. There are reports suggesting thatthe convalescent serum was used to treatpatients in recent COVID-19 outbreak in China. Although many details are notavailable yet, the information from current epidemic in china suggeststhat using convalescent plasma reducedviral load and was safe. The clinical efficacy of this particular approach isnot yet established against COVID19, nevertheless convalescent plasma remains to be our onlyhope, given that the limited State resources supporting the health sector wouldsoon turn out to be a spoiler.
Risks and Benefits. COVID-19 convalescent serum can be usedeither as a prophylactic measure to prevent disease in high risk population,for instance, Healthcare professionals and people with underlying co-morbid conditions. It can also bestrategized as a treatment therapy by administering high titer “neutralizingantibody sera” already been clinically demonstrated elsewhere, for thetreatment of Rabies, Hepatitis B etc. This approach is also being used forsevere respiratory syncytial virus (RSV) in high risk infants. Therapeutically,convalescent sera can be administered to those with COVID-19 disease in an effortto reduce symptoms and improve overall prognosis. Based on the alreadyavailable information, it can be safely concluded that convalescent sera aremore effective in preventing disease progression than to treat patients suffering fromcritical and irreversible respiratory organ damage. Though, Mesenchymal StemCell therapy alone or coupled with immunosuppressants/ steroids or other drugs,in presence or absence of Convalescent sera therapy (depending on the patient’sconditions) could restore the pulmonary function.
There are potential risks associated with this therapy, oneof the common health hazard associated is the generalized reactions toinadvertent infectious agents present in donor’s blood. Serum sickness remainsas additional hazard manifested by immunological reactions to serum componentsof a “donor/recovered patient”. Other risks associated with this approachinclude but not limited to transfusion related acute lung injury in patientswith pulmonary disease, antibody dependent enhancement of infection, andattenuation of natural immune response to SARS-COV-2 after exposure toneutralizing antibodies. Although minimal, the specific immunological risksmentioned here are theoretical in nature and would require assessment on ageneral basis possibly in a clinical trial scenario. Current available datawith convalescent sera in other Coronaviruses like SARS and MERS suggest thatbenefits outweigh the risks given the high mortality rate associated with thedisease and the nature of the epidemic.
A general note on where we stand.
Convalescent sera harvesting and administration for COVID-19 requires some basic facilitiesand expertise, well placed at our primary healthcare centers. As common as, a)Labs equipped to process Serum for serological assays, determining antibodytiter and antibody mediated virus neutralization assays, b) Human resource tomodify/tailor available FDA approved prophylaxis and therapeutic protocols toaccess efficacy of an intervention and measuring immune responses/viralclearance c) Blood banking facilities and few Aphaeresis equipments to storeand process donated serum d) Institutional review board for regulatory andethical approval to administer such a therapeutic protocol. With the approval by US Food and drugadministration (US-FDA) granted in 4th week of March, the Convalescent SeraTherapy procedure is likely to be adopted by various hospitals across the UnitedStates. The powerful regulatory authority-FDA, as one may call it has setstrict guidelines in bringing the procedure into practice. US-FDA has allowedemergency use of serum for treating COVID-19 at multiple centers like MontSinai hospital, Albert Einstein College of medicine and University ofWashington. Several trails were also conducted by Zhejiang University School ofmedicine during current pandemic and if one has to believe the scientistsinvolved, convalescent plasma has been effective in decreasing viral load inpatients.
Given the scenario that we are in, it’s of absoluteimportance to expedite the process of adopting the procedure with whateverlittle results it may yield, for all that it could still turn out to be betterthan other therapeutic strategies. Assuming that almost all the frontline drugslike Tocilizumab, Sirukumab, Prednisolone or Hydroxy-chloroquine will soon beoff the shelves due to limited supply. The wisdom must foster, with prodigiousresponsibility to take a lead and to make headway with determined decisions,serving a game-changer script of this millennium. All it needs a coordinatedeffort from healthcare professionals, backup volunteers such as researchers anda centralized command commissioned by Specialist Doctors with relevantexpertise, having known few of them, be sure the Kashmir has it what it needsat this time of crisis.
Mushtaq A. Beigh, PhD is Assistant Professor, Department ofNanotechnology, University of Kashmir