Passive immunity refers to the infusion of antibodies (either polyclonal antibodies in the form of convalescent plasma, or engineered monoclonal antibodies).  The goal is to neutralize viral particles, reduce viral replication, and thereby improve clinical outcomes.  This is a promising theory, but it requires evidentiary support in the form of randomized controlled trials.  So far, seven RCTs have tested this concept.  What have they found?

four RCTs on convalescent plasma

Li L et al.  Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19  (JAMA)

This was an open-label, multicenter RCT involving 103 hospitalized patients with moderate or severe disease (respiratory distress, hypoxemia, or more severe features).^​1​  Patients who already had high titers of antibodies against the COVID-19 spike protein receptor binding domain were excluded from the study.  The median interval between symptom onset and randomization was ~30 days.  Baseline clinical features are as follows:

Half of the patients were treated with 4-13 ml/kg of convalescent plasma.  The administered plasma was tested and selected to ensure that donors had high levels of antibodies against the spike protein receptor binding domain.  Plasma was also selected using typing (with the ABO system) and crossmatching.   

Convalescent plasma did increase the rate of virus clearance.  However, none of the clinical endpoints were significantly altered:

Two patients treated with convalescent plasma developed transfusion reactions, one of which was severe. 

Agarwal A et al.  Convalescent plasma in the management of moderate COVID-19 in adults in India:  open label phase II multicentre randomized controlled trial (PLACID trial, BMJ)

This was an open-label, multicenter RCT involving 464 patients hospitalized with moderate disease as defined by PaO2/FiO2 of 200-300 (78% were on low-flow oxygen and 22% were on high-flow oxygen or noninvasive ventilation).^​2​  Patients were enrolled a median of 8 days after symptom onset.  Baseline clinical features are as follows:

Half of patients were treated with two doses of 200 ml convalescent plasma, administered one day apart.  Evaluation of donors for the presence of neutralizing antibody became available about halfway through the study.  Retrospective analysis of banked plasma demonstrated that 64% of plasma donors had a neutralizing antibody titer >1:20 (with a median titer of 1:40). 

The primary endpoint was death or deterioration in oxygenation to PaO2/FiO2 <100.  The rate of deterioration was 19% in the plasma group versus 18% in the control group.  Secondary endpoints showed an improvement in symptom resolution (possibly a placebo effect in this nonblinded trial), but no difference in hard endpoints (e.g., intubation):

84% of patients had detectable neutralizing antibody at study entry.  The median antibody titer was 1:90, which is a higher titer than antibodies present in the convalescent plasma.  Administration of convalescent plasma had no impact on the level of neutralizing antibody in the two patient groups over time (figure below).  There were also no differences in other laboratory values (CRP, ferritin, D-dimer, or lactate dehydrogenase).

Subgroup analysis was performed to investigate whether administration of plasma with higher titers of antibody might have improved clinical endpoints.  No differences were detected.  A subgroup analysis likewise failed to detect benefit among patients who lacked neutralizing antibodies at enrollment: 

Three patients were deemed to have died “possibly related to convalescent plasma transfusion,” which would yield a 1% mortality for this intervention.

Simonovich VA et al.  A randomized trial of convalescent plasma in COVID-19 severe pneumonia  (PLASMAR trial, NEJM)

This is a double-blind, placebo-controlled multicenter trial involving 228 patients admitted with hypoxemia yet not requiring intubation.^​3​  Patients were enrolled a median of 8 days after symptom onset.  Baseline characteristics were as follows:

Two-thirds of patients were randomized to receive ~500 ml of convalescent plasma.  Plasma donors were required to have an antibody titer of at least 1:400.  Donated plasma had a median antibody titer of 1:3200.  Plasma administration did achieve a statistically significant increase in neutralizing antibody two days after administration of the plasma, although this difference rapidly dissipated.

There were no differences detected in any of the clinical endpoints:

Subgroup analysis detected no benefits, not even among patients whose antibodies were initially undetectable: 

Libster R et al.  Early high-titer plasma therapy to prevent severe COVID-19 in older adults  (INFANT-COVID-19, NEJM)

This is a double-blind, multicenter RCT investigating the administration of convalescent plasma with high IgG titer within 72 hours of symptom onset.^​4​  The study selected patients at higher risk of disease progression (>75YO or >65YO plus a comorbidity) who were experiencing mild symptoms for <48 hours.  Baseline characteristics were as follows:

Patients were randomized to placebo or 250 ml of convalescent plasma with an IgG titer >1:1,000 against COVID spike protein.  To obtain this plasma they screened numerous potential donors and selected those with the highest 28th percentile of antibody titers.  The day after infusion, patients who received convalescent plasma had higher antibody titers:

The primary endpoint was development of “severe respiratory disease” which was defined as either hypoxemia (<93% saturation on room air) or tachypnea (>30 breaths/minute).  Deterioration was less likely in patients who received convalescent plasma (16% vs. 31%, p = 0.04, fragility index of one). Secondary endpoints didn’t reach statistical significance:

This study is promising, but it still fails to demonstrate improvement in a meaningful, patient-centered endpoint.  If convalescent plasma improves the patient’s saturation from 90% to 94% or reduces the respiratory rate from 32 breaths/minute to 28 breaths/minute – does that actually matter?  Is that a clinically significant improvement, or merely a statistically significant one?  It’s hard to tell.  The study was stopped prematurely due to slow recruitment, so the clinical outcomes are a bit murky. 

Joyner MJ et al. Convalescent plasma antibody levels and the risk of death from COVID-19 (NEJM)

This study isn't an RCT, but bears discussion because it was published in the New England Journal and will receive lots of attention. It is a retrospective correlational study performed using data from a network of hospitals across the United States that administered convalescent plasma.^​5​ Patients who received plasma with higher antibody titers tended to have lower mortality – which might seem to imply that convalescent plasma causes lower mortality.

That sounds exciting, but remember that this is a retrospective correlational study. There were major differences between patients who received low-titer plasma versus high-titer plasma (table below). Patients receiving low-titer plasma were sicker based on a number of different metrics and they also received different treatments (they were more likely to receive hydroxychloroquine). It's unclear why these differences arose, but they might relate to regional variation in blood banking procedures and population composition.

In efforts to account for these confounding variables, the data was analyzed using three different models. The conclusions vary depending on which model you use! Using the base model, high-titer plasma correlated with lower mortality (green highlights below). However, using Model 3, there were no significant mortality differences (the confidence intervals include 1). The fact that results were not reproducible when analyzed using different models reveals that these results are not reliable.

This study is a great example of why we need randomized controlled trials. Retrospective correlational studies such as this one leave us stumbling through a minefield of confounding variables, grasping at different statistical models in the hopes that they could magically eliminate all confounding factors. Unfortunately, given the depth of bias in this dataset, it's impossible to remove all sources of confounding (because it's likely that additional confounding variables exist that were not measured).

The authors performed some additional sub-group analyses and eventually concluded that convalescent plasma strongly reduced mortality among non-intubated patients (relative risk of 0.66, see above). If this were actually true, it should have already been revealed by the RCTs above. It's unclear what this highly confounded study is supposed to add to previously performed RCTs, other than confusion.

three RCTs on monoclonal antibodies

Weinreich DM et al.  REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19 (NEJM)

This is a double-blind, multicenter RCT investigating the use of a cocktail of two monoclonal antibodies (REGN, a.k.a. Regeneron).^​6​  Outpatients were recruited who had less than seven days of symptoms.  Patients were generally young and very mildly ill:

Patients were randomized into three groups:  placebo, 2.4 grams REGN, or 8 grams REGN.  There was no primary endpoint, but instead the authors tested a lot of endpoints and focused on the positive ones.  REGN did reduce viral titers among patients who initially lacked antibodies (about half of the patients):

However, this didn’t translate into any measurable clinical improvements.  Specifically, there was no significant difference in the rate of patients seeking further medical care (not even among the subgroup of patients who were initially lacking antibodies).  Most patients were relatively young and did fine clinically, regardless of which therapy they received.

ACTIV-3/TICO LY-CoV555 Study Group:  A neutralizing monoclonal antibody for hospitalized patients with COVID-19  (ACTIV-3, NEJM)

This is a multicenter, placebo-controlled RCT evaluating the efficacy of a monoclonal antibody (bamlanivimab) among patients hospitalized with COVID-19.^​7​  The median delay of therapy after symptom onset was seven days.  Baseline characteristics were as follows:

The study was stopped prematurely due to futility.  No differences were detected in any clinical endpoint (table below).  No benefit was found in any subgroups either (including the subgroup of patients with symptoms for less than five days).

Chan P et al.  SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with COVID-19  (BLAZE-1, NEJM)

This is a blinded, multicenter RCT evaluating a monoclonal antibody (bamlanivimab) among outpatients.  Most patients were young and had symptoms for a median of 4 days:

The primary endpoint was change in viral load at 11 days.  There was a reduction of viral load but only in in patients receiving the lower dose of bamlanivimab. This may well have been a statistical anomaly (based on the multiple comparisons involved). 

Patients treated with bamlanivimab had slightly fewer symptoms at some timepoints (figure below).  The difference is statistically marginal and of dubious clinical significance:

The most notable secondary endpoint was “hospitalization” rate.  The authors redefined the term “hospitalization” during the course of the study to mean either hospital admission or an emergency department visit.  Using this creative flex, the authors managed to obtain a statistically significant improvement in “hospitalization” rates (from 6% to 2%, p = 0.02). 

It remains a mystery how many of these patients were actually admitted to the hospital.

conclusions on monoclonal antibody cocktails

To date, no study has revealed definite clinical benefit from monoclonal antibody cocktails.  Furthermore, over time, additional problems with these drugs are likely to emerge:

• It’s unclear whether monoclonal antibodies will be effective against newer forms of COVID-19 (e.g., the B.1.1.7 strain). 
• Administration of monoclonal antibodies could prevent vaccines from working (by causing rapid clearance of spike protein).

Given a lack of any clear effectiveness of these medications, it’s strange that they have received emergency authorization and are being used clinically.  Further studies may be useful, but it’s likely that ongoing mutation of the virus will outrun these monoclonal antibodies (regardless of whether they worked in the first place).

conclusions on convalescent plasma

Risks of convalescent plasma are greater than risks of monoclonal antibodies.  As with any blood product, these risks include the transmission of viral infections and anaphylaxis.  A large series at the Mayo Clinic reported a significant rate of adverse events, including allergic reactions, volume overload, and TRALI (transfusion related acute lung injury):^​8​

Convalescent plasma appears ineffective for patients admitted to the hospital with COVID pneumonia.  By the time patients are admitted, most are already in the process of producing antibodies and clearing the virus.  Much of the clinical illness at this point may be immunopathological, so a slight improvement in viral clearance may not matter clinically.

The INFANT-COVID study does raise the possibility that high-titer convalescent plasma could be beneficial if given very early (<72 hours after symptom onset) with a selected high-risk cohort of patients.  This concept merits further investigation.  However, even in this study, where they did everything perfectly – there was still no statistically significant improvement in patient-centered clinical endpoints. 

All convalescent plasma is not created equal.  For example, different donors may have different levels of neutralizing antibodies against varying strains of the virus.  It’s likely that quality control may be more lax outside the context of a randomized controlled trial.  Consequently, the benefits of ad hoc convalescent plasma programs may be variable and potentially inferior to the results reported above. 

why neither monoclonal antibodies nor convalescent plasma is likely to be very helpful

It’s increasingly clear that the administration of monoclonal antibodies or convalescent plasma late in the disease course (e.g., after hospitalization) is ineffective.  By this timepoint, patients are already beginning to clear the virus.  Furthermore, much of the clinical illness may be immunopathological, rather than resulting directly from viral load. 

This has pushed interest towards early intervention.  However, numerous problems bedevil early intervention as well:

• Patients need to be treated very rapidly (e.g., <72 hours after symptoms).  Achieving this requires that patients seek prompt medical attention, are quickly tested for COVID, and that tests turn around rapidly. 
• Most patients with COVID will do fine without any medical therapy.  Therefore, treating minimally symptomatic patients early on will result in treating tons of patients who would have done perfectly well without any treatment.  For patients who would have done well without therapy, treatment exposes them to potential risks without any benefits. 
• Early intervention requires broadly targeting all at-risk patients (rather than the small fraction who develop severe disease). As the pandemic expands, it will become logistically impossible to treat all of these patients (e.g. convalescent plasma stores will be exhausted).

• To date, no prospective RCTs have demonstrated robust, meaningful clinical benefit from either convalescent plasma or monoclonal antibodies.
• By the time patients are admitted to the hospital, most are already producing antibodies and clearing the virus.  There doesn’t appear to be any clinical benefit from immunoglobulin administration at that timepoint.
• Convalescent plasma exposes patients to a variety of risks, including transmission of blood-borne pathogens, volume overload, transfusion-related acute lung injury, and anaphylaxis. 
• Administration of convalescent plasma and monoclonal antibodies may divert resources from more important activities (e.g., management of ill patients, vaccine distribution). 
• Given potential harms and lack of proven benefit, further use of convalescent plasma or monoclonal immunoglobulins should be restricted to the context of randomized clinical trials. 

related

• Convalescent plasma
  • Convalescent plasma in COVID-19 patients (PLACID trial) – St. Emlyn's Blog, by Simon Carley
  • The PlasmAr Trial – Convalescent Plasma vs Placebo (RebelEM, Salim Rezaie)
• Bamlanivimab
  • I'm so confused about bamlanivimab (PulmCrit)
  • BLAZE-1 trial (RebelEM, Salim Rezaie)
• REGN (Regeneron)
  • No evidence that REGN-COV2 (Regeneron) antibody cocktail has clinical benefits (RebelEM, Anand Swaminathan)

references

1. 1.

   Li L, Zhang W, Hu Y, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020;324(5):460-470. doi:10.1001/jama.2020.10044
2. 2.

   Agarwal A, Mukherjee A, Kumar G, et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020;371:m3939. doi:10.1136/bmj.m3939
3. 3.

   Simonovich V, Burgos P, Scibona P, et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. Published online November 24, 2020. doi:10.1056/NEJMoa2031304
4. 4.

   Libster R, Pérez M, Wappner D, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. Published online January 6, 2021. doi:10.1056/NEJMoa2033700
5. 5.

   Joyner M et al. Convalescent Plasma Antibody Levels and the Risk of Death from COVID-19. N Engl J Med. https://www.nejm.org/doi/full/10.1056/NEJMoa2031893
6. 6.

   Weinreich D, Sivapalasingam S, Norton T, et al. REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19. N Engl J Med. Published online December 17, 2020. doi:10.1056/NEJMoa2035002
7. 7.

   Chen P, Nirula A, Heller B, et al. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. Published online October 28, 2020. doi:10.1056/NEJMoa2029849
8. 8.

   Joyner M, Bruno K, Klassen S, et al. Safety Update: COVID-19 Convalescent Plasma in 20,000 Hospitalized Patients. Mayo Clin Proc. 2020;95(9):1888-1897. doi:10.1016/j.mayocp.2020.06.028