Intravenous Immunoglobulins for the Treatment of Covid-19 Patients: a Clinical Trial

Emerging and re-emerging viruses are a significant threat to global public health. Since the
end of 2019, Chinese authorities have reported a cluster of human pneumonia cases in Wuhan
City, China and the disease was designated as coronavirus disease 2019 (COVID-19). These
cases showed symptoms such as fever, dyspnea, and were diagnosed as viral pneumonia. Whole
genome sequencing results show the causative agent is a novel coronavirus, which was
initially named 2019-nCoV by World Health Organization (WHO). Later the International
Committee on Taxonomy of Viruses (ICTV) officially designate the virus as SARS CoV-2
(Coronaviridae Study Group of the International Committee on Taxonomy of Viruses, 2020),
although many virologists argue that HCoV-19 is more appropriate . As of 24 February 2020,
79,331 laboratory-confirmed cases have been reported to the WHO globally, with 77,262 cases
in China, including 2,595 deaths. In addition, twenty-nine other countries have confirmed
imported cases of SARS-CoV-2 infection raising great public health concerns worldwide.
SARS-CoV-2 represents the seventh coronavirus that is known to cause human disease.
Coronaviruses (CoVs) are a group of large and enveloped viruses with positive sense,
single-stranded RNA genomes. Previously identified human CoVs that cause human disease
include severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory
syndrome coronavirus (MERS-CoV) . SARS-CoV and MERS-CoV infection can result in life
threatening disease and have pandemic potential. During 2002-2003, SARS-CoV initially emerged
in China and swiftly spread to other parts of the world, causing > 8,000 infections and
approximately 800 related deaths worldwide. In 2012, MERS-CoV was first identified in the
Middle East and then spread to other countries. As of November 2019, a total of 2,494 MERS
cases with 858 related deaths have been recorded in 27 countries globally. Notably, new cases
of MERS-CoV infecting humans are still being reported recently. Both SARS-CoV and MERS-CoV
are zoonotic pathogens originating from animals. Detailed investigations indicate that
SARS-CoV is transmitted from civet cats to humans and MERS-CoV from dromedary camels to
humans. The source of SARS-CoV-2, however, is still under investigation, but linked to a wet
animal market. There is no specific antiviral treatment recommended for COVID-19, and no
vaccine is currently available. The treatment is symptomatic, and oxygen therapy represents
the major treatment intervention for patients with severe infection. Mechanical ventilation
may be necessary in cases of respiratory failure refractory to oxygen therapy, whereas
hemodynamic support is essential for managing septic shock. Although no antiviral treatments
have been approved, several approaches have been proposed such as lopinavir/ritonavir
(400/100 mg every 12 hours), chloroquine (500 mg every 12 hours), and hydroxychloroquine (200
mg every 12 hours). Alpha-interferon (e.g., 5 million units by aerosol inhalation twice per
day) is also used. Preclinical studies suggested that remdesivir (GS5734) - an inhibitor of
RNA polymerase with in vitro activity against multiple RNA viruses, including Ebola - could
be effective for both prophylaxis and therapy of HCoVs infections. This drug was positively
tested in a rhesus macaque model of MERS-CoV infection. One dose of 200 mL convalescent
plasma (CP) derived from recently recovered donors with the neutralizing antibody titers
above 1:640 was transfused to the patients as an addition to maximal supportive care and
antiviral agents. Despite a lack of completed clinical trials, the FDA has granted this
temporary authorization under its Investigational New Drug Applicants (eINDS) exemption, in
light of the extent and nature of the current public health threat that COVID-19 represents.
A number of pre-clinical and clinical trials around use of plasma from patients who have
recovered are underway, however, and there are some promising signs that convalescent plasma
could indeed be effective against SARS-CoV-2.

Apart from convalescent plasma, small scale concentrates of immunoglobulins prepared from
convalescent plasma collections provide higher potency and greater consistency than
individual units. The feasibility of production of large scale of diseases specific
immunoglobulins concentrates can considered for longer term, based on the course of epidemic,
access to large numbers of suitable plasma collections, and the available infrastructure for
manufacturing such products under GMP.

• Convalescent plasma can be used for serum therapy but it has further limitations which
include:

- Separate plasma for separate blood groups: In case of plasma, it seems difficult to
arrange the required blood groups separately for serum therapy, while immunoglobulins
can be injected randomly to individual of different blood groups.

- Serum Sickness & Blood Proteins reactogencity: Only 18% of plasma constitutes
immunoglobulins required for passive immunization. Remaining portions contain proteins
that pose to reactogenicity threat to patient safety.

- Dose volume: In case of plasma therapy, 200-300ml of plasma required for single patient
that depends upon number of recovered patients available. While in case of
immunoglobulins used in virus therapy require only 3-5ml per day.

- Risk of microbial contamination: As most portion of plasma contain proteins and proteins
are more prone to contamination risk. It is difficult to handle the serum to maintain
its sterility while immunoglobulins are far less prone to sterility issues.

- Potency: Concentrated immunoglobulins are far more potent as it shows targeted response.
In case of plasma, proteins fractions pose a delayed response.

- Targeted Population: Plasma therapy is subjected to moderate to severe patients
specially, while all effected individuals can take benefit of immunoglobulin therapy
because dose of immunoglobulins can be controlled.