High-titer convalescent plasma reduced COVID-19 symptom severity in green monkeys

By Dr. Liji Thomas, MDOct 16 2020

Even as the world attempts to limp back to a semblance of normalcy after the initial phase of the COVID-19 pandemic, a massive second wave threatens to swamp healthcare facilities again.

As scientists scramble to find effective vaccines and antivirals for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recent study published on the preprint server bioRxiv* in October 2020 reports that the use of convalescent plasma to treat COVID-19 disease early in the course of the illness may be among the best available strategies at present.

Study: Use of convalescent serum reduces severity of COVID-19 in nonhuman primates. Image Credit: Felipe Caparros

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

The Current State of CP Therapy

Historically, convalescent plasma has been used to treat many infectious diseases, including influenza. At present, many centers in the US, for instance, have also resorted to this strategy to treat COVID-19. However, the fact that these are not part of a randomized clinical trial has made many clinicians skeptical of this therapeutic agent's real value.

Many trials have thus been set up to examine the efficiency and safety of CP in COVID-19 patients with acute illness. While most investigators concur that CP is possibly beneficial, there are many unknowns, including the effective dose, the route of viral exposure, and the incubation period's actual length. This points to the need for experimental studies using treated subjects and controls to understand this therapy's value and risks.

Some studies using rodent models show CP to be beneficial, but they did not shed light on how it affects disease parameters in this infection. Earlier studies in non-human primates (NHPs) infected with MERS have shown the benefit of hyperimmune plasma, but no such studies exist in NHPs for CP.

CP Mitigates Clinical Disease Markers

The current study examines convalescent plasma's role containing high antibody titers in an infected NHP model. It thus seeks to offer direct proof that CP is useful as a tool to manage this pandemic. The researchers used their newly developed African green monkey model for this study since it recapitulates the characteristic features of human COVID-19.

Groups of monkeys were inoculated with SARS-CoV-2 and then treated with pooled CP, classified as either high or low, concerning their neutralizing antibody titer. They found that animals treated with high-titer CP showed lower viral loads in the lungs than those treated with low-titer CP and untreated controls.

Animals in the high-dose CP group also had less severe lung lesions and lower levels of clotting factors and other inflammatory markers, compared to either the group treated with low-dose CP or controls. These markers include clotting times, fibrinogen, cytokine levels, and platelet counts.

There was no discernible difference in viral load or tissue pathology among the monkeys that were treated with CP containing low titers of nAbs and the untreated controls. Despite this, they found that overall, all monkeys treated with CP had lower viral load in the lung tissue, less severe lesions in the lungs, and lower levels of the disease indicators compared to controls.

This shows that the CP exerted an antiviral effect, shown as the absence of infectious virus in the bronchoalveolar lavage fluid from all treated animals, and less severe lung disease, even when the CP contained only a low level of nAbs. However, the best strategy appears to be to use CP containing a high level of potent nAbs.

Other Benefits of CP

The researchers admit that the antiviral effect may be due not only to the presence of nAbs but also other antibody-related effects and antiviral effects caused by other soluble factors generated as a result of the natural response to the viral infection. Moreover, a meta-analysis of all available information on the thousands of patients who have been given CP in this pandemic indicates its benefit in reducing the duration of hospital stay, as well as a good safety profile. It does not seem to be associated with antibody-dependent enhancement (ADE).

The latter is a valid fear given earlier research on rhesus monkeys who were vaccinated with SARS-CoV-2 spike vaccine and developed worsening lung disease due to ADE.

Timing and Titer Are Crucial

Some recent papers show the influence of timing and antibody titer in determining the usefulness of CP therapy since patients with advanced disease at the time of CP initiation tend to recover less well compared to those who receive it early in the course of the disease.

A large clinical trial from India (using donor CP with a median titer of 1:40), which was prematurely terminated for want of preliminary evidence of benefit, shows that this may be derived only when the CP has a high median antibody titer. In the current study, the low dose group had a median titer of ~1:128 and the high dose group ~1:2048.

Conclusion

The study sums up: "Our data support human studies suggesting that convalescent plasma therapy is an effective strategy if donors with a high level of antibodies against SARS-CoV-2 are employed and if recipients are at an early stage of the disease."

CP's advantage is its ready availability, which may allow clinicians to effectively treat COVID-19 patients early and thus prevent an acute surge in severely ill patients, overwhelming intensive care units, and hospitals. Its correct use may bridge the current gap between demand and supply for more effective drugs in the current pandemic.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources