Examining Convalescent Plasma for SARS, MERS, and SARS-CoV-2

April 25, 2020
Michaela Fleming

Strategic Alliance Partners | <b>Society of Infectious Diseases Pharmacists</b>

In part 1 of our interview, Ryan W. Stevens, PharmD, BCIDP, provides an overview of how convalescent plasma has been used to treat infectious diseases including coronaviruses.

Segment description: In part 1 of our interview Ryan W. Stevens, PharmD, BCIDP, infectious diseases and antimicrobial stewardship pharmacist, Mayo Clinic, provides an overview of how convalescent plasma has been used to treat infectious diseases including coronaviruses.

Interview transcript (modified slightly for readability):

Contagion®: Thanks for joining us for another Contagion coronavirus video. Today we're joined by Dr. Ryan Stevens who is a member of the Society of Infectious Diseases Pharmacists and recently presented a webinar on convalescent plasma. Thanks so much for joining us. So let's just get started. Can you describe the mechanism of action of convalescent plasma?

Stevens: Sure, so, convalescent plasma and the idea of giving it as a therapeutic for viral infections, it really stems from the idea of harvesting the adaptive immune system from 1 patient and then tasking that to the second patient who's in acute viral phase of the illness. So, essentially, you take a patient who's had an infection with the virus and has recovered, that has been presumed or proven to produce antibodies that pathogen. In the case of SARS-CoV-2 this antibody development generally takes place with seroconversion somewhere between 8 and 21 days since the beginning of the infection. After this person has been proven to have the infection and has fully recovered, you take their blood and you harvest plasma from the blood. Then this plasma is then administered the second patient who's in an acute viral phase the illness, thereby passing the adaptive immune system from patient 1 on to patient 2.

Contagion®: So how is convalescent plasma been used for other infectious diseases and specifically for other coronaviruses?

Yeah, so there's a lot out there on this. That would make sense because convalescent plasma is really one of the oldest therapies in infectious disease we have. It dates back into the pre antibiotic era, as far as 1892 when it was used for the treatment of diphtheria, with serum actually being harvested from various animals. Over the years it's been used for a lot of different infections with Spanish flu, measles, and pertussis, but most recently, it's been used in 4 viral illnesses since the year 2000. So, one is influenza A H1N1 one and one in 2009 and one of Ebola in 2015. For the sake of what we're talking about here with SARS-CoV-2 and COVID-19, we should look at it in the context of other coronaviruses. That would include SARS-CoV-1 in 2003, and then the Middle Eastern respiratory syndrome coronavirus in 2012.

So, with regards to SARS-CoV-1 in 2003 outbreak in Hong Kong, there was a study where they administered convalescent plasma to 80 patients with SARS-CoV-1. They look for the primary outcome of discharge from the hospital by day 22. They found that 33 of their 80 patients met this primary outcome, which is about 41%. There were 2 important findings that came out of this study with regards to convalescent plasma. The first is that they found that patients that received convalescent plasma within 14 days of the onset of their symptoms were more likely to reach primary outcome of discharge by day 22.

This would make sense given that we know that coronavirus has 2 immediate phases. The first is the viral phase where the virus is present. The second is more of an immune activation phase. So it makes sense that got the convalescent plasma during the viral phase to have a better outcome. Then the second finding that they found was that patients that were PCR positive by a nasal pharyngeal PCR, but zero negative for antibodies at the time they received the convalescent plasma were actually more likely to reach the primary outcome as well. And again, this makes sense because we're passing the adaptive immunity from one patient onto a second. If the second patient hasn't developed their own active immunity, yet, it would make sense that they would be more likely to potentially experience the outcome of discharge by day 22. If we look at the Middle East respiratory syndrome coronavirus, there's some interesting data that came out of that as well. In 1 very, very small study, they administered convalescent to 3 patients with MERS-CoV. They looked for the rate of earliest seroconversion, so seroconversion to the recipient within a few days. What they found was that there was only 1 of the 3 patients that actually had early seroconversion. That 1 patient was also consequently, the only patient received convalescent plasma with a neutralizing antibody titer of ≥1:80. So the important finding that came out of this study is the idea that the neutralizing antibody titer of the donor may actually impact the seroconversion and thereby potentially the immunity.

Contagion®: What do we know so far about convalescent plasma for COVID-19?

Stevens: What we know is relatively limited. Our knowledge of convalescent plasma and its efficacy in SARS-CoV-2 or the treatment of COVID-19 comes from 3 very small studies. Two were small, uncontrolled studies. This is a cumulative 19 patients across these 2 papers. All patients that received it, all 19 of them, were either severely or critically ill at the time they received the convalescent plasma, and the regimens that they receive varied widely depending on the paper. So 1 used a single unit of convalescent plasma which is about 200 milliliters, with no neutralizing antibody titer of >1:640. That's a very high neutralizing antibody titer. The second used 400 milliliters which was administered in 2 separate 1 unit infusions with a neutralizing antibody titer of >1:40 and an IgG titer of >1:1000. Now, the first study didn't actually check titers with donors, but they administered non-standard volumes. This was more of a safety reason. They administered anywhere between 220 and 2400 milliliters of convalescent plasma.

Another important thing to note is that most of the patients who have received concomitant antiviral therapy, you see that looking at the ritonavir, hydroxychloroquine or other therapies, at the same time or before receiving convalescent plasma, and corticosteroid receipt is also very common in this population.

If we look at the duration symptoms before they presented to the hospital all 19, presented within roughly 2 to 4 days of the development symptoms. They all received convalescent plasma therapy within about 12 to 20 days since the onset of symptoms. All of these papers report various forms of clinical, radiographic, or virologic outcomes. All of them report favorable outcomes. Some of the things that were reported were things like resolution of radiographic infiltrates, or improvement in symptoms and clinical symptoms as defined by various symptom scores, and improvements in inflammatory markers like CRP and IL-6, and increases in antibody titers in recipients. One of the studies specifically reported the rate of conversion of the nasal pharyngeal PCR to a negative result, which also showed favorable outcomes. Most notably is that all 19 of these patients survived at the time that the papers were written. They represent a little bit of reporting bias, but I think it is an encouraging finding. It's important that we note though, that all the papers to date all lack control groups. There was a lot of other confounders that I've mentioned like concurrent antiviral therapies, so the variability in different regimens. We have to interpret the data with caution, but I think when we couple these 19 cases with the data we have from SARS-CoV-1, I'm optimistic about the use of convalescent plasma at this point.