Monoclonal antibody cocktail – An Exceptional game changer for COVID treatment in India

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Immunity against a pathogen occurs either naturally or as a result of exposure to it. Vaccination is a biological procedure that stimulates the immune system of a person. It protects against the infectious agent after subsequent exposure to pathogenic diseases. Immunization has incredible potential to activate and destroy the invading illness in the human immune system. The immunization provides a more flexible and highly target-specific response by creating two kinds of lymphocytes, B and T.

In B lymphocytes, B cells create specific antibodies to identify and remove pathogenic agents. On the contrary, monoclonal antibodies are antibodies which are purposely generated in the laboratory to tackle a given disease. The two antibodies in Roche's antibody cocktail 'Casirivimab' and 'Imdevimab' are targeted specifically against the SARS-CoV-2 protein. They block the virus from targetting into human cells and can be a potential "game changer" to combat Covid-19.

Introduction

Immunity refers to the protection against the generated infections and diseases. The pathogens are the microorganism that can cause disease in the body, such as a bacterium, virus, parasite, or fungus. The immune system refers to immune cells and molecules, and their efforts are referred to as immunological reactions in response to any etiological event. As a consequence, both internal and exterior risks are protected by the immune system. In reaction to bacteria and other external stimuli, immune reactions are typically induced (Chumakov et al., 2021). It is classified into two different types: innate and adaptive (Table 1). Another word for innate immunity is natural or native immunity. It is the defense of every infectious agent in the human body, such viruses and bacteria, at the moment they enter. It normally involves a number of metabolic and cellular responses that react to bacteria and their metabolites to remove them from the body. The innate immune system occasionally fails to eradicate infectious germs because it cannot identify all illnesses.  

It also helps to trigger other immune system cells, by supplying signals for the adaptive immune system in the form of chemical signals (cytokines) or degradation components of antigens Rubin et al., 2021) This is referred to as 'antigenic presentation,' and without these indications the adaptive immune system cannot be engaged. A more diversified and focused protection has been produced by the adapted immune system. On the other hand, the adaptive immune system is slow and can take several days to activate two types of important cells, namely B cells and T cells (Sette & Crotty, 2021). The two forms of adaptive immune responses are humoral immune reactions and immunological reactions mediated by the cells. Humoral immunity is the most frequent type of immune response to outside pathogens. Inflammatory immunological responses result from antibodies produced by activated B-cells (Cotsapas et al., 2021). Antibodies are proteins which are created in response to invading pathogenic diseases such as bacteria, protozoa, fungal diseases or virus by B-lymphocytes. These invasive microorganisms are known as antigens. A critical component of the immune system is the antibodies produced in reaction to the antigen of the infection that operate as soldiers in the body defense mechanism. Antibodies or soldiers were taught to identify a single antigen in our system. The antigen and the antibody have a lock and key link, which implies that the antigens are extremely specific and that the illness for which they have been developed is neutralized (Arunachalam et al., 2021). There are two types of antibodies. One kind is membrane-bound and works as an antigen receptor on the B cell surface. The other kind is found in blood circulation and connective tissue, preventing the entry and propagation of infection. The initial IgM antibodies are produced and after a few weeks they disappear (Ko et al., 2021). At the same time or 2-3 days later, IgG antibodies are generated and may remain for months or years.

Table 1. Comparison between Innate and Adaptive immune response

Features

Innate immune response

Adaptive immune response

Time of response

The initial line of defense against any infection entering

The second line of defense, which begins in 6 - 8 days

Mechanism

Scavenging action or creating barriers (skin and outer epithelial surface) or secreting interferon and cytokines provide protection.

T cells (cellular response) and B cells are the two kinds of white blood cells involved (antibody response)

Memory

No

Yes

Diversity

Narrow

Wide

Cell-mediated immune response

Cellular immunity is attributable to T cells or lymphocytes. The aim of cell-mediated immunity includes intracellular micro-organisms, viruses and some intracellular bacteria. Infected cells are supported by direct death or phagocytosis by cell-mediated immunity (Holmdahl et al., 2021). T cells detect quickly proliferate cells infected with a certain virus to battle infection. Furthermore, T cells are classified under CD4+ and CD8+. CD4+ helps T cells recruit other cells in the immune system by producing cytokines. B-cells grow into plasma cells and create antibodies to neutrally control the pathogen. Cytokines encourage the growth of the B cells on the other hand, cells CD8+ cytotoxic T directly kill infected cells. CD8+ cytotoxic T cells consequently halt the infection and kill the virus-infected cells (yang et al., 2021). The number of T and B cells diminishes once the invader has been fought and the infection is over. On the other hand, Memory cells are a long-lasting T and B memory reservoir. These lymphocytes are inert until they are infected with the same illness the following time. This time memory cells develop an immune response considerably faster and more efficient. These memory cells functioned fast by boosting an antibody response to destroy the infection or virus and are the vital component for long-term preservation of the adaptive immune system.

Vaccine

A vaccine is a biological substance which, after repeated exposure to the pathogen, induces immune responses and protects against or causes infectious agents or infections, and also diseases. Vaccines comprise a specific organism's (antigen) weakened or inactive section that produces a body's immune reaction. Any immunogens mentioned below may be included in a vaccine. Inactivated killed pathogen (alive, reproducing, but not pathogenic); pathogen attenuated. Recombinant (hosted and purified viral antigen); recombinant protein (synthetic antigen parts); subunit (pathogen derived); Vectored (viral pathogen for a virus which is not dangerous); Coding for a viral protein injecting nucleic acid (DNA or RNA). In order to detect the illness when it is encountered in the wild, the vaccines safely offer any of the immunologists indicated above in the immune system. The kind of immune response, safety, protection and protection length are all determined by the content and delivery of the immunogen (Razai et al., 2021). The vaccination doesn't cause the disease in the individual receiving the disease but stimulates your immune system to respond to the virus. The body is therefore trained to withstand this particular organism producing a sickness by preserving the memory of the infection to be able to combat it swiftly when and if it becomes exposed. Different vaccines and their efficacy against COVID – 19 are indexed in Table 2.

Table 2. Vaccines available for COVID-19 across globe (https://www.moneycontrol.com/)

Vaccine Name

Type of Vaccine

Manufacturer

No. of Doses

Duration between 1st and 2nd Dose

Covaxin

Inactivated Virus

Bharat Biotech

2

4-6 Week

Pfizer - BNT162b2

mRNA

Pfizer, Inc., and BioNTech

2

21 Days

Moderna - mRNA-1273

mRNA

ModernaTX, Inc

2

28 Days

Oxford-AstraZeneca - AZD1222

Viral Vector

Serum Institute of India (Covishield)

2

12-16 Week

Sputnik V (Gamaleya)

Viral Vector

RDIF and Panacea Biotech (in India)

2

21 Days

Johnson and Johnson (Janssen) - JNJ-78436735

Viral Vector

Janssen Pharmaceuticals Companies of Johnson & Johnson

1

Data Not Available

CoronaVac (Sinovac)

Inactivated Virus

Sinovac Life Sciences, Beijing, China

2

21 Days

Sinopharm

Inactivated Virus

Beijing Bio-Institute of Biological Products Co Ltd

2

3-4 Weeks

 

Monoclonal antibody cocktail

Monoclonal antibodies are proteins that are generated in a laboratory that imitate the ability of the immune system to combat diseases such as viruses (Sivapalasingam et al., 2021). The cocktail antibody of Casirivimab and Imdevimab contains the monoclonal antibodies generated in the laboratory using recombinant DNA technology of human immunoglobulin G-1 (IgG1). It was invented by Regeneron, a medicines business company. This monoclonal antibody cocktail is specially designed to block the spike protein of SARS-CoV-2 from binding and penetrating human cells. This combination still works against the most frequent varieties and can neutralize novel kinds. A monoclonal antibody cocktail provides great protection against coronavirus for people who live with COVID-19 infections. Roche India and Cipla pharmaceutical companies are responsible for marketing in India.  In adults and patients in pediatrics (12 or older, weighing at least 40 kg) who have been demonstrated to become infected with SARS-COV2 and are very vulnerable to treatment of mild to moderate COVID-19 disease 2019.

The total cost of each patient dosage would be Rs. 59,750/- per patient, including all taxes, of 1200 mg in combination (600 mg Casirivimab and 600 mg Imdevimab). It has to be maintained at temperatures between 2°C and 8 °C. The final Phase 3 trial in high risk non-hospitalized COVID-19 patients met their primary endpoint, which shows that investigational REGEN-COVTM (Casirivimab with Imdevimab) significantly reduced the risk of hospitalization or death by 70% (1,200 mg) and by 71% (2,400 mg). On the other hand, the sensitivity (Table 3) of the two FDA-approved monoclonal antibodies was reduced by many variant strains (https://newsroom.regeneron.com/).

Table 3. Pseudovirus neutralisation for COVID Variant Substitutions with casirivimab and imdevimab

Key Substitutions Tested

Lineage with Spike Protein Substitution

Origin

Fold Reduction in Susceptibility

N501Y

B.1.1.7

UK

No change

K417N, E484K, N501Y

B.1.351

South Africa 

No change

K417T + E484K

P.1

Brazil

No change

L452R

B.1.427/B.1.429

California

No change

E484K

B.1.526

New York 

No change

Authorized Emergency Use of Monoclonal antibody cocktail

In adult and pediatric individuals (12 years of age and under 40 kg) with positive outcomes from direct SARS-CoV-2 viral tests and high risk of further development in severe COVID-19 and/or hospitalizations, REGEN-COV is licensed for therapy for mild to moderated COVID-19. In patients who are hospitalized for COVID-19, require oxygen therapy for COVID-19 or require an increase in baseline oxygen rate as a result of COVID-19 due in those for the chronic oxygen therapy because of subordinate non-COVID-19 related co-morbidity, REGEN-COV (Casirivimab in combination with Imdevimab) is not authorized for use. In those hospitalized because to COVID-19, the benefits of REGEN-COV treatment were not evident.

Conclusion

According to Roche India and Cipla, the antibody cocktail (Casirivimab and Imdevimab) are already available in India, and a second batch will be available by mid-June. They might help a total of 2,00,000 individuals. With its great distribution capability, Cipla distributes the product throughout the country. The medicines may be obtained at leading hospitals and COVID therapy institutes. In India, the CDSCO (Central Drugs Standard Control Organization) has given an Emergency Use Approval (EUA) to the mixture of the antibody cocktail. In the United States, it has also won an EUA and other nations of the European Union.

References

  1. Arunachalam, P. S., Walls, A. C., Golden, N., Atyeo, C., Fischinger, S., Li, C., ... & Pulendran, B. (2021). Adjuvanting a subunit COVID-19 vaccine to induce protective immunity. Nature, 1-6.
  2. Chumakov, K., Avidan, M. S., Benn, C. S., Bertozzi, S. M., Blatt, L., Chang, A. Y., & Gallo, R. C. (2021). Old vaccines for new infections: Exploiting innate immunity to control COVID-19 and prevent future pandemics. Proceedings of the National Academy of Sciences, 118(21).
  3. Cotsapas, C., Saarela, J., Farmer, J. R., Scaria, V., & Abraham, R. S. (2021). Do monogenic inborn errors of immunity cause susceptibility to severe COVID-19?. The Journal of Clinical Investigation.
  4. Holmdahl, I., Kahn, R., Hay, J. A., Buckee, C. O., & Mina, M. J. (2021). Estimation of Transmission of COVID-19 in Simulated Nursing Homes With Frequent Testing and Immunity-Based Staffing. JAMA Network Open, 4(5), e2110071-e2110071.
  5. https://newsroom.regeneron.com/news-releases/news-release-details/phase-3-trial-shows-regen-covtm-casirivimab-imdevimab-antibody
  6. https://www.moneycontrol.com/news/trends/health-trends/covid-19-vaccines-in-india-and-around-the-world-6970511.html
  7. Ko, S. H., Bayat Mokhtari, E., Mudvari, P., Stein, S., Stringham, C. D., Wagner, D., ... & Boritz, E. A. (2021). High-throughput, single-copy sequencing reveals SARS-CoV-2 spike variants coincident with mounting humoral immunity during acute COVID-19. PLoS pathogens, 17(4), e1009431.
  8. Razai, M. S., Osama, T., McKechnie, D. G., & Majeed, A. (2021). Covid-19 vaccine hesitancy among ethnic minority groups.
  9. Rubin, R. (2021). COVID-19 Vaccines vs Variants—Determining How Much Immunity Is Enough. Jama, 325(13), 1241-1243.
  10. Sette, A., & Crotty, S. (2021). Adaptive immunity to SARS-CoV-2 and COVID-19. Cell.
  11. Sivapalasingam, S., Saviolakis, G. A., Kulcsar, K., Nakamura, A., Conrad, T., Hassanein, M., ... & Lipsich, L. Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle Eastern Respiratory Syndrome Coronavirus (MERS-CoV). The Journal of infectious diseases, jiab036.
  12. Yang, R., Deng, Y., Huang, B., Huang, L., Lin, A., Li, Y., ... & Tan, W. (2021). A core-shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity. Signal Transduction and Targeted Therapy, 6(1), 1-10.

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