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Winter 2021 - Critical Care

The Promise of COVID-19 Hyperimmune Immune Globulin Therapy

In the early months of the COVID-19 pandemic, attention was understandably focused on three critical priorities: public health measures intended to prevent disease transmission, development of protective vaccines against the SARS-CoV-2 virus, and potential treatments to reduce severe complications and deaths, particularly for the roughly 40 percent of adults whose age or compromised health status places them at relatively high risk of hospitalization and death. 

Among the more widely publicized investigational treatments is COVID-19 convalescent plasma (CCP) collected by apheresis from fully recovered COVID-19 patients. Just as they did for the plasma donor, anti-SARS-CoV-2 antibodies in CCP directly neutralize the virus or act to facilitate viral clearance. Anecdotal evidence from past acute respiratory viral disease pandemics — SARS, MERS, Argentine hemorrhagic fever, even the 1918 Spanish flu — suggest early transfusion of one to two units of CCP could potentially reduce mortality.1

To date, however, conflicting early findings from a number of matched-control and placebo-controlled trials have led to controversy over whether the roughly two grams to four grams of immune globulin G (IgG)* in a unit or two of CCP can confer meaningful survival benefit in hospitalized COVID-19 patients. Nevertheless, in August, the U.S. Food and Drug Administration (FDA) granted CCP emergency use authorization for essentially unrestricted use in hospitalized COVID-19 patients.2

* As well as smaller gram quantities of IgM and IgA

Meanwhile, the National Institutes of Allergy and Infectious Diseases (NIAID) has joined with several companies in development of anti-SARS-CoV-2 monoclonal antibodies (MAbs), based on what agency director Anthony Fauci, MD, describes as “their direct antiviral effect” that acts to “block the virus from entering its target cell in the body and hence interrupt the course of infection.” They do so by targeting the highly conserved receptor binding domain of the virus’s critical spike protein that enables it to gain entry to targeted cells and commandeer their genetic apparatus to replicate itself (Figure 1). 

The first preparations to enter clinical trials comprise either a single MAb or “cocktails” of two potent anti-spike protein MAbs selected from thousands of anti-SARS-CoV-2 antibodies identified from recovered COVID-19 patients or produced in mice that have been genetically modified to have a human immune system. Furthest along in development are MAb candidates developed by Regeneron Pharmaceuticals and Eli Lilly. While results are not yet available from trials in hospitalized patients, both companies have reported highly encouraging preliminary findings from separate studies of two-MAb “cocktails” in symptomatic COVID-19 outpatients, including significantly reduced viral load and lower rates of COVID-19 medical visits than those experienced in the placebo control groups.

The third class of investigational COVID-19 antibody preparations will have a familiar ring for emergency room and infectious disease specialists: concentrated COVID-19 hyperimmune IgG (COVID-Ig) prepared from large pools of high-titer CCP. In early October, NIAID announced the initiation of the multinational Phase 3 Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) trial to test the safety, tolerability and efficacy of high-dose intravenous COVID-Ig. Five hundred hospitalized patients are being randomized to receive COVID-Ig in conjunction with remdesivir, or remdesivir alone. In a first-of-its-kind collaboration, potent virus-neutralizing COVID-Ig is being supplied by four leading manufacturers of standard or hyperimmune polyvalent IgG therapies: Grifols, CSL Behring, Takeda Pharmaceuticals and Emergent BioSolutions.**

** Other plasma products companies participating in this “COVIg-19 Plasma Alliance” include ADMA Biologics, Biotest, BPL, GC Pharma, LFB, Liminal BioSciences, Octapharma and Sanquin. Two other major plasma fractionators, Kedrion Biopharma and Kamada, are also collaborating to develop their own COVID-Ig preparation.

As of this writing, NIAID and industry collaborators are also finalizing the design of a large-scale trial to assess whether COVID-Ig can reduce the rate of hospitalization and other medical encounters in earlier-stage COVID-19 patients exhibiting mild to moderate symptoms. With support from the U.S. Department of Defense, at least one trial is planned as well to evaluate COVID-Ig as postexposure prophylaxis treatment for frontline healthcare and other high-risk populations at high risk of COVID-19 infection.3

So, with CCP, COVID-Ig and monoclonal antibody preparations, we have not one but three potential anti-SARS-CoV-2 antibody-based treatments currently or soon to be investigated for 1) hospitalized COVID-19 patients, 2) symptomatic nonhospitalized COVID-19 patients, in particular those at high risk for progressing to severe disease, and 3) populations exposed or at increased risk of exposure to COVID-19.

Clinical trials will be completed and findings reported over the coming months. But in the meantime, can we surmise anything in advance about the real-world prospects for these three distinct antibody therapies in specific treatment settings? It turns out the answer is yes.

It’s COVID-Ig or MAbs for COVID-19 Prevention and Early Treatment

In concert with cellular immune defenses, a humoral immune response is critical to help clear SARS-CoV-2 infection.4  Neutralizing anti-SARS-CoV-2 antibodies act to block the spike protein receptor binding domain (RBD) that fuses with surface ACE2 receptors to enable viral entry into host cells. 

But not unlike the pathogenesis of SARS, the first coronavirus pandemic that swept through southeast Asia in 2003, there is a weak link in our immune response: a median of roughly 14 days elapses between infection and seroconversion. A week after initial symptoms appear, most COVID-19 patients still have no detectable IgG antibodies against the virus. That extended time lag before humoral immunity finally kicks in, coupled with a lethargic cellular immune response in some infected individuals,2 gives this novel coronavirus a big head start during its early viremic phase (Figure 2), resulting in a potentially serious or lethal disease course in more susceptible individuals. 

The principle of closing that time gap and “nipping the infection in the bud” was the impetus for the development of multiple licensed hyperimmune IgG products for postexposure prophylaxis, including those for rabies (HyperRAB S/D, KEDRAB), hepatitis B (HyperHEP S/D, Nabi-HB) and varicella zoster (VARIZIG). All contain high titers of neutralizing antibodies purified from recovered or vaccine-immunized plasma donors. Monoclonal antibody preparations have similarly proven effective for prevention of lower respiratory tract infection caused by respiratory syncytial virus (RSV) in susceptible pediatric patients (SYNAGIS [palivizumab]) and, very recently, for treatment to reduce mortality in patients with symptomatic Zaire ebolavirus infection (INMAZEB). 

To produce each batch of COVID-Ig, thousands of CCP donations are individually screened to assure presence of significant IgG antibody titers against SARS-CoV-2, similar to screening of potential CCP donor units for transfusion. But following pooling and processing of CCP units into COVID-Ig, gram-for-gram the final hyperimmune IgG product contains several times more SARS-CoV-2 neutralizing antibodies than is found in the plasma units from most donors who have recovered from COVID-19.5

Why is this? In part, it is likely because anti-SARS-CoV-2 IgG titers generally identified by ELISA binding assays donor CCP units do not always fully correlate with viral neutralizing titers. In tests of CCP units from 26 recovered patient donors, for example, one research team reported just three of those donor units demonstrated effective blockade of SARS-CoV-2 spike protein RBD binding to ACE2 receptors.6

The variability in anti-SARS-CoV-2 antibody and neutralizing titers from one unit of donor CCP to the next raises a basic question about the clinical utility of donor CCP therapy, both in the setting of postexposure prophylaxis and early treatment of high-risk symptomatic COVID-19 patients. Now that COVID-Ig with consistently high viral neutralizing titers is available for clinical investigation, is it still valid or advisable to separately evaluate single-donor convalescent plasma whose SARS-CoV-2 neutralizing capacity and potential protective efficacy are known to vary widely from one individual unit “dose” to the next?

Consider, for example, a multicenter clinical trial currently randomizing 500 high-risk adults who have been exposed to COVID-19 to transfusion of a single 200 mL to 250 mL unit of CCP with SARS-CoV-2 antibody titers of ≥1:320, or curiously, a unit of conventional nonimmune donor plasma.7 Now that plasma fractionators are processing thousands of units of high-titer CCP into clinical quantities of hyperimmune COVID-Ig with consistent high-titer, broad-spectrum neutralizing anti-SARS-CoV-2 antibody, would it not make sense to include COVID-Ig as a second active treatment arm?*** The same reasoning could equally apply to other large-scale clinical trials currently investigating whether a single unit of CCP can reduce hospitalizations or death in symptomatic adult outpatients with COVID-19.8,9

*** A similar argument could be made for including a highly neutralizing investigational MAb preparation as a second active treatment arm. An example is Eli Lilly’s LY-CoV555, currently being evaluated in the 2,400-subject placebo-controlled Phase III BLAZE-2 trial (NCT04497987) in nursing home residents and staff at facilities with a high risk of SARS-CoV-2 exposure.

There are other more pragmatic questions about the use of CCP for prevention or early treatment of COVID-19. Is it safe, practical or even feasible to potentially perform many thousands of plasma transfusion procedures each day in individuals in the community who have been exposed to COVID-19, or are sick but still at home with mild to moderate COVID-19 symptoms? Table 1 identifies a number of potential advantages of a standardized COVID-Ig preparation over CCP in a real-world clinical setting.

CCP, COVID-Ig and MAbs in Hospitalized COVID-19 Patients

The much-anticipated NIAID-sponsored ITAC trial investigating high-dose (400 mg/kg body weight) COVID-Ig in hospitalized COVID-19 patients started subject enrollment in early October and is projected to be completed in July 2021. With support from Grifols, Octapharma and LFB, a number of other studies are also evaluating high-dose standard intravenous immune globulin (IVIG) in severely ill COVID-19 patients to test the hypothesis that the immunomodulatory properties of IVIG can limit the progression of acute respiratory distress syndrome (ARDS) and other major complications attributed to the inflammatory cytokine-mediated “cytokine storm” phenomenon seen in severely ill patients.10,11

Clinical testing of MAbs for treatment of hospitalized COVID-19 patients has not started out well. In late October, a Phase III randomized placebo-controlled clinical trial evaluating intravenous infusion of Eli Lilly’s investigational anti-SARS-CoV-2 MAb (LY-CoV555) in hospitalized COVID-19 patients was halted early after a review of unblinded data showed little likelihood of therapeutic value. Shortly after the start of a separate inpatient trial of REGN-COV2, its two-antibody MAb cocktail, Regeneron, suspended further enrollment of hospitalized subjects requiring high-flow oxygen or mechanical ventilation pending further analysis. The company explained this decision was based on “a potential safety signal and an unfavorable risk-benefit profile” identified by the trial’s Independent Data Monitoring Committee (IDMC). However, the IDMC recommended continuation of enrollment of other COVID-19 inpatients on low-flow oxygen or who do not require oxygen. 

Thus far, investigations of CCP account for nearly all published findings involving SARS-CoV-2 antibody therapy for hospitalized COVID-19 patients. They include an uncontrolled 20,000-patient case series,12 a number of matched-control studies13 all reporting mortality odds ratios clearly favoring CCP, and several randomized controlled trials,11 most notably a 464-subject trial that found no difference in mortality, regardless of the presence or absence of neutralizing antibodies in administered CCP.

The cumulative evidence to date points to two likely predictors of clinical benefit that should apply for any of the three investigational antibody treatment modalities:

• Antibody administration as early as possible following initial development of symptoms or hospital admission. This finding is the basis for the ITAC/COVID-Ig trial’s inclusion criterion that subjects must have had COVID-19 symptoms for 12 days or fewer; and

• Absence of or a very low measured patient serum anti-SARS-CoV-2 antibody titer at enrollment. It is reasonable if not self-evident that patients who have already seroconverted and are producing their own anti-SARS-CoV-2 antibody are less likely to benefit from infusion of exogenous antiviral antibodies.

In addition, published findings to date strongly indicate that in instances when CCP is transfused within the first three days of hospital admission, all-cause mortality is significantly lower in patients given CCP units with higher anti-SARS-CoV-2 antibody or neutralizing titers.14,15

Polyvalent Immune Globulin: An Added Advantage?

Particularly for people whose age, medical history or underlying comorbidities place them at higher risk for progression to severe disease, both COVID-Ig and spike protein-targeted MAbs appear highly promising for postexposure prophylaxis and early treatment of symptomatic COVID-19. But that said, a case can be made for added potential therapeutic benefit of COVIG-Ig as it comprises not one or two but literally thousands of unique antibodies targeting different viral epitopes. “This multiplicity of natural anti-SARS-CoV-2 antibodies can tie up the virus in ways that reduce the infection and make it more difficult to escape through mutation,” said Laura Saward, PhD, Emergent BioSolutions’ senior vice president, therapeutics. 

Recognizing that this natural polyvalent antiviral activity could translate into improved clinical efficacy, South San Francisco-based GigaGen has applied proprietary technology to produce a “recombinant hyperimmune” containing a mixture of 12,500 anti-coronavirus antibodies isolated from CCP of numerous recovered donors.16  Called “GIGA-2050,” this COVID-19 antibody-based drug candidate is claimed to be 100 times more protective than high-titer CCP using live virus neutralization assays. 

GigaGen recently announced it has initiated large-scale manufacturing of GIGA-2050, and it expects to begin clinical trials in early 2021. Remaining to be seen is whether this ground-breaking anti-COVID-19 recombinant hyperimmune can be manufactured economically, particularly in relation to extraordinarily efficient bioreactors that we also know as convalescent plasma donors.

In any case, dosing COVID-19 patients with significant gram quantities of human plasma-derived polyvalent COVID-Ig may bring yet one more potential therapeutic bonus to the table: potent anti-inflammatory activity mediated by thousands of immunomodulatory IgG antibodies that are always present in the circulation of healthy donors. 

For people at risk for suffering the worst ravages of this disease, there are too many unknowns to confidently predict whether high-titer, human plasma-derived COVID-Ig will turn out to be more, less or similarly protective as the drug makers’ concentrates of one or two highly neutralizing monoclonal antibodies. We will have to wait patiently for results of clinical trials. But one would be foolish to bet against what is essentially the successful human humoral immune response to COVID-19 in a bottle.


1. Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systemic review and exploratory meta-analysis. JID 2015 Jan 1;211:80-90.

2. FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment, Another Achievement in Administration’s Fight Against Pandemic. Accessed Oct. 29, 2020, at

3. DoD funds industry trio to develop hyperimmune globulin product for COVID-19. Accessed Oct. 23, 2020, at

4. Silva TF, Tomiotto-Pellissier F, Sanfelice RA, et al. A 21st century evil: immunopathology and new therapies of COVID-19. Front Immunol 2020 Oct 27.

5. National Institutes of Health. NIH clinical trial testing hyperimmune intravenous immunoglobulin plus remdesivir to trat COVID-19 begins. Accessed Oct. 24, 2020, at

6. Chen X, Li R, Pan Z, et al. Human monoclonal antibodies block the binding of SARS-CoV2 spike protein to angiotensin converting enzyme 2 receptor. Cell Molec Immunol 2020;17:647-9.

7. Johns Hopkins University (sponsor). Convalescent Plasma to Stem Coronavirus (CSSC-001). Accessed Oct. 27, 2020, at

8. Johns Hopkins University (sponsor). Convalescent Plasma to Limit SARS-CoV-2 Associated Complications (CSSC-004). Accessed Oct. 27, 2020, at

9. Stanford University (sponsor). Convalescent Plasma in Outpatients with COVID-19 (C3PO). Accessed 10/27/2020 at

10. A Study to Evaluate the Safety and Efficacy of High Dose IVIG Plus Standard Medical Treatment (SMT) Versus SMT Alone in Participants in ICU with COVID-19. (NCT04480424). Accessed Oct. 29, 2020, at

11. A Study of Standard of Care (SOC) Plus IVIG Compared to SOC Alone in the Treatment of COVID-19 Infection. (NCT04411667). Accessed Oct. 29, 2020, at

12. Joyner MJ, Bruno KA, Klassen SA, et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proceed 2020 Sep;95(9):1888-97.

13. Klassen SA, Senefeld JW, Johnson PW, et al. Evidence favoring the efficacy of convalescent plasma for COVID-19 therapy. medRxiv 2020 Oct 29.

14. Salazar E, Christensen PA, Graviss EA, et al. Treatment of COVID-19 patients with convalescent plasma reveals a signal of significantly decreased mortality. Am J Pathol 2020 Nov;190(11):2290-2303.

15. Joyner MJ, Senefeld JW, Klassen SA, et al. Effect of convalescent plasma on mortality among hospitalized patients with COVID-19: initial three-month experience. medRxiv 2020 Aug 12.

16. GigaGen announced publication of research describing a new class of drugs, recombinant hyperimmunes, including its novel COVID-19 therapy, GIGA-2050. Accessed Oct. 30, 2020, at

Keith Berman, MPH, MBA
Keith Berman, MPH, MBA, is the founder of Health Research Associates, providing reimbursement consulting, business development and market research services to biopharmaceutical, blood product and medical device manufacturers and suppliers. He also serves as editor of International Blood/Plasma News, a blood products industry newsletter.