A Study of COVID 19 Convalescent Plasma in High Risk Patients With COVID 19 Infection

Hypothesis or Research Question • Is convalescent plasma from patients previously infected
with COVID-19 an effective treatment option for high risk patients through the utilization of
passive immunity?

o Is the mortality rate reduced through the use of this treatment?

Background Passive antibody therapy involves the administration of antibodies to a given
agent to a susceptible individual for the purpose of preventing or treating an infectious
disease due to that agent. In contrast, active vaccination requires the induction of an
immune response that takes time to develop and varies depending on the vaccine recipient.
Some immunocompromised patients fail to achieve an adequate immune response. Thus, passive
antibody administration is the only means of providing immediate immunity to susceptible
persons and immunity of any measurable kind for highly immunocompromised patients.

Passive antibody therapy has a storied history going back to the 1890s and was the only means
of treating certain infectious diseases prior to the development of antimicrobial therapy in
the 1940s (1,2). Experience from prior outbreaks with other coronaviruses, such as SARS-CoV-1
shows that such convalescent plasma contains neutralizing antibodies to the relevant virus
(3). In the case of SARS-CoV-2, the anticipated mechanism of action by which passive antibody
therapy would mediate protection is viral neutralization. However, other mechanisms may be
possible, such as antibody dependent cellular cytotoxicity and/or phagocytosis. Convalescent
serum was also used in the 2013 African Ebola epidemic. A small non-randomized study in
Sierra Leone revealed a significant increase in survival for those treated with convalescent
whole blood relative to those who received standard treatment (4).

The only antibody type that is currently available for immediate use is that found in human
convalescent plasma. As more individuals contract COVID-19 and recover, the number of
potential donors will continue to increase.

A general principle of passive antibody therapy is that it is more effective when used for
prophylaxis than for treatment of disease. When used for therapy, antibody is most effective
when administered shortly after the onset of symptoms. The reason for temporal variation in
efficacy is not well understood but could reflect that passive antibody works by neutralizing
the initial inoculum, which is likely to be much smaller than that of established disease.
Another explanation is that antibody works by modifying the inflammatory response, which is
also easier during the initial immune response, which may be asymptomatic (5). As an example,
passive antibody therapy for pneumococcal pneumonia was most effective when administered
shortly after the onset of symptoms and there was no benefit if antibody administration was
delayed past the third day of disease (6). In this context, we seek to treat patients who are
sick enough to warrant hospitalization but prior to the onset of overwhelming disease
including advanced systemic inflammatory response, sepsis, and/or ARDS. We hypothesize that
convalescent plasma will be more effective given earlier in the hospital course and we aim to
maximize the overall potential population benefit by directing the plasma to patients who at
presentation are predicted to be at high risk but before they are in advanced overwhelming
disease. We aim to start plasma therapy within 24 hours of admission or when high risk
features are first evident.

For passive antibody therapy to be effective, a sufficient amount of antibody must be
administered. When given to a susceptible person, this antibody will circulate in the blood,
reach tissues and provide protection against infection. Depending on the antibody amount and
composition, the protection conferred by the transferred immunoglobulin can last from weeks
to months.

In the 21st century, there were two other epidemics with coronaviruses that were associated
with high mortality, SARS1 in 2003 and MERS in 2012. In both outbreaks, the high mortality
and absence of effective therapies led to the use of convalescent plasma. The largest study
involved the treatment of 80 patients in Hong Kong with SARS (7). Patients treated before day
14 had improved prognosis defined by discharge from hospital before day 22, consistent with
the notion that earlier administration is more likely to be effective. In addition, those who
were RT-PCR positive and seronegative for coronavirus at the time of therapy had improved
prognosis. There is also some anecdotal information on the use of convalescent plasma in
seriously ill individuals. Three patients with SARS in Taiwan were treated with 500 ml of
convalescent plasma, resulting in a reduction in plasma virus titer and each survived (8).
Three patients with MERS in South Korea were treated with convalescent plasma, but only two
of the recipients had neutralizing antibody in their plasma (9). The latter study highlights
a challenge in using convalescent plasma, namely, that some who recover from viral disease
may not have high titers of neutralizing antibody (10). Consistent with this point, an
analysis of 99 samples of convalescent sera from patients with MERS showed that 87 had
neutralizing antibody with a geometric mean titer of 1:61. This suggests that antibody
declines with time and/or that few patients make high titer responses.

It is also possible that other types of non-neutralizing antibodies are made that contribute
to protection and recovery as described for other viral diseases (11). There are reports that
convalescent plasma was used for therapy of patients with COVID-19 in China during the
current outbreak (http://www.xinhuanet.com/english/2020-02/28/c_138828177.htm). Although few
details are available from the Chinese experience and published studies involved small
numbers of patients, the available information suggests that convalescent plasma
administration reduces viral load and was safe.