Covid-19 and Made in India Vaccines

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PARLIAMENT1 LIBRARY AND REFERENCE, RESEARCH, DOCUMENTATION AND INFORMATION SERVICE (LARRDIS) ------RESEARCH AND INFORMATION DIVISION

RESEARCH NOTE LARRDIS NO. 1/2021/RN JULY 2021

At a Glance  The Indian Covid-19 Vaccine Development Mission known as the ‘Covid Suraksha Mission’ was launched in November 2020.

 Within 114 days of starting vaccination, India reached the 17 crore mark- a target achieved faster than USA and China.

 A way to ensure adequate supply and equitable and affordable distribution of vaccines,

medicines and medical technologies, is to remove some of the barriers created by the intellectual property rights (IPRs), particularly in the area of technology transfer and to encourage manufacturers and research groups to work together towards a common goal.

 COVID-19 is expected to usher significant attention towards the Indian vaccine market from investors, government, institutions and regulatory agencies.

 The Indian vaccine manufacturers, with large production capacities and technical expertise, are expected to benefit from the growing popularity of the contract

manufacturing of vaccines.

This Research Note is intended to serve as a background aid to the Hon’ble Members of Parliament. It is for restricted circulation and not for publication in any form. ------[Prepared by Social Affairs Wing; Officers associated with the preparation – Ms Deepti Aggarwal, Intern; Shri Ranganathan S Sharma, Joint Director (23034756); supervised by Dr Vatsala Joshi, Director (23034738) and Smt Kalpana Sharma, Additional Secretary (23034845). Feedback is welcome and may be sent to [email protected]]

Introduction

The Covid-19 pandemic has severely disrupted the health infrastructure of almost all the countries posed an existential threat to the mankind. The need of the hour was to develop a treatment to combat this deadly disease and researchers identified vaccine as a potent solution. Historically, it has taken years to develop a vaccine to cure a disease but in the case of Corona virus, vaccines have been developed in a record time and governments around the world are fast tracking the production of vaccines to vaccinate its citizens.

Vaccines are the primary intervention strategy in the control of coronavirus transmission and infection. Several methods are available for the development of a vaccine against SARS-CoV-2, including the use of inactive or live-attenuated viruses, virus-like particles (VLPs), viral vectors, and protein-based, DNA-based, and mRNA-based vaccines. However, the development of a vaccine typically spans 10–15 years. Owing to the rapid identification and publication of the SARS-CoV-2 gene sequence, it was only a matter of months before the first vaccine candidate was ready for clinical testing. Currently, more than 60 SARS-CoV-2 vaccines are being developed at different clinical trial phases. The following sections provide a brief outline of the main platforms for the development of a SARS-CoV-2 vaccine, namely inactivated, live-attenuated, and recombinant vaccines.

Vaccine Categories Vaccines, which are presently being studied for COVID-19, can be categorised into the following five groups:

1. Genetic material (DNA or RNA) based vaccines: These use one or more corona virus’s genes to produce an immune response. 1 Moderna (USA), Pfizer/Biontech (Germany), Moderna/National Institute of Allergies And Infectious Diseases (US) have been produced using this technology.

2. Vector-based vaccines: These use other viruses (e.g., adenovirus, which typically causes common cold) to deliver coronavirus genes into cells and produce an immune response. 2 Astrazeneca/University Of Oxford (UK), Cansino Biologics Inc. (China), Janssen/Johnson & Johnson (USA) have been produced using this technology.

3. Protein-based vaccines: These use a coronavirus protein or a protein fragment to produce an immune response.

4. Weakened or inactivated virus vaccines: These use a weakened or activated form of coronavirus to produce an immune response. 3Sinovac (China) and Beijing Institute of Biological Products (China) have been produced using this technology.

5. Repurposed vaccines: These are already approved and used for other diseases and are currently being tested for their role in protection against the COVID-19 virus.

1 https://www.gavi.org/vaccineswork/covid-19-vaccine-race?gclid=Cj0KCQjwub- HBhCyARIsAPctr7w1DxewR_eP_oncNg0eivZbamkb9cAkvgGWQ1ZG3ny7gPJIlz31-gsaAo7kEALw_wcB

2 ibid 3 ibid 2

Vaccine in India

4 The Indian Covid-19 Vaccine Development Mission known as the ‘Covid Suraksha Mission’ was launched in November 2020, with a focus on accelerating an end- to-end Vaccine development starting from Preclinical Development to Clinical trials to Manufacturing and Regulatory facilitation. The Mission was envisaged for making available safe and efficacious COVID-19 Vaccine which is affordable and accessible. The mission received budgetary approvals of Rs 900 crore for 12 months. On January 16, 2021, vaccination began in India. Within 114 days of starting vaccination, India reached the 17 crore mark- a target achieved faster than USA and China. For the ongoing vaccination drive, 35.6 Crore vaccines have been procured. These include 6.6 Crore vaccines received from PM Cares Fund. 1 Crore Covishield vaccines from the Global Alliance for Vaccines and Immunizations (GAVI) COVAX facility, 12 Crore were procured for Phase II and 16 Crore were procured for Phase III by Govt. of India. The projected availability of vaccines in India is given below:

Production/Availability of doses ( in crores) August-December 2021

3% COVISHIELD 5% 7% COVAXIN 35% 9% Bio E Sub unit vaccine 2% Zydus Cadila DNA vaccine SII - NOVAVAX 14% BB Nasal vaccine

25% Gennova mRNA vaccine Sputnik vaccine

Covaxin has been indigenously developed in India while the remaining vaccines are being produced under technology transfer agreement. 5 COVAXIN, India's indigenous COVID-19 vaccine by Bharat Biotech is developed in collaboration with the Indian Council of Medical Research (ICMR) - National Institute of Virology (NIV). This indigenous,

4 Annexure 1 NITI Research Note on Pharmaceutical Industry and vaccines 5 https://www.bharatbiotech.com/covaxin.html 3 inactivated vaccine is developed and manufactured in Bharat Biotech's BSL-3 (6Bio-Safety Level 3) high containment facility. The vaccine is developed using Whole-Virion Inactivated Vero Cell derived platform technology. Inactivated vaccines do not replicate and are therefore unlikely to revert and cause pathological effects. They contain dead virus, incapable of infecting people but still able to instruct the immune system to mount a defensive reaction against an infection.

 7Covaxin works by teaching the immune system to make antibodies against the SARS-CoV-2 corona virus. The antibodies attach to viral proteins, such as the so-called spike proteins that stud its surface.  Researchers produced large stocks of the corona viruses, they doused them with a chemical called beta-propiolactone. The8inactivated viruses was taken and mixed them with a small amount of an aluminum-based compound called an adjuvant.  Adjuvants stimulate the immune system to boost its response to a vaccine.  Once inside the body, the inactivated viruses are swallowed up by a type of immune cell called an antigen-presenting cell.  Another type of immune cells ‘B cells’, also encounter the inactivated corona virus.  Some B cells surface proteins latch up the corona virus and produce Antibodies along with T Cells.

Challenges

India, although being the largest manufacturer of vaccines, providing protection against Covid-19 has been a challenge for the limited availability of enough doses for the large population in a short span of time. The process of vaccine development includes pre-clinical studies followed by clinical studies. The pre-clinical development is performed in the laboratory employing animal models to assess the safety of the candidate vaccine and its immunogenicity (ability to provoke an immune response). The clinical development component includes a series of human clinical trials, for assessment of safety, immunogenicity and efficacy of the vaccine candidate prior to human immunisation. The traditional vaccine development process is a long-drawn and time intensive process requiring anywhere between 5-10 years.

6 https://consteril.com/biosafety-levels-difference/: Biological Safety Levels (BSL) are a series of protections relegated to autoclave-related activities that take place in particular biological labs. They are individual safeguards designed to protect laboratory personnel, as well as the surrounding environment and community. These levels, which are ranked from one to four, are selected based on the agents or organisms that are being researched or worked on in any given laboratory setting. For example, a basic lab setting specializing in the research of nonlethal agents that pose a minimal potential threat to lab workers and the environment are generally considered BSL-1—the lowest biosafety lab level. A specialized research laboratory that deals with potentially deadly infectious agents like Ebola would be designated as BSL-4—the highest and most stringent level. 7 https://www.nytimes.com/interactive/2021/health/bharat-biotech-covid-19-vaccine.html 8 Inactivated viruses have been used for over a century. Jonas Salk used them to create his polio vaccine in the 1950s, and they’re the bases for vaccines against other diseases including rabies and hepatitis A. 4

With the surge observed during the second wave of Covid-19 pandemic, there is eagerness for vaccination9. The reasons behind the unequitable vaccine availability are as follows:10

 Production of vaccines is a complex and time-taking process as it involves handling of biological products and setting up of specialized infrastructure.

 Each type of vaccine platform requires a different set of raw materials, which also need to be scaled-up, commensurate to vaccine production.

 Availability of Good manufacturing practice (GMP) grade materials, small molecules and enzymes for mRNA11 Vaccine production; cell lines and adjuvants for inactivated and protein subunit vaccines; consumables such as single use bags, filters etc., are some of the critical requirements that have been highlighted by the manufacturer.

 Vaccine production and distribution is limited to and controlled by a few pharmaceutical giants.

 Most production is currently concentrated in high-income countries; production by middle- income countries has been happening mostly through licensing or technology transfer agreements.

Central Drugs Standard Control Organisation (CDSCO)12 regulates Quality, Safety and Efficacy of New Drugs including Vaccines as per the provisions of New Drugs and Clinical Trials Rules, 2019 under Drugs and Cosmetics Act, 1940 and has no role in the grant of intellectual property protection or waiver under Patent Act 1970 pertaining to production of Vaccines. CDSCO with respect to production of COVID-19 Vaccines which may be deemed to be Novel Vaccines are placed as follows:

1. Vaccine Technology: Technology transfer plays a key role for manufacturing of vaccines in the country. Technology transfer is required for providing efficiency of process and consistency of Quality in the manufacturing of COVID-19 Vaccine which includes characterization, validation, and assurance of batch to batch consistency and compliance to the Good manufacturing practice (GMP) as per the requirements of Drugs and Cosmetics Rules, 1945 and WHO Technical Report Series (TRS) 961 Annex 7. Without proper Tech transfer the time taken for manufacturing the vaccine in the country may be extended for want of process validation.

2. Starting Materials/components: COVID-19 vaccines are being manufactured using

9 Inputs from the Ministry of Health

10 The Pharmaceutical Industry in India: Challenges 11 https://www.genome.gov/genetics-glossary/messenger-rna: Messenger RNA (mRNA) is a single-stranded RNA molecule that is complementary to one of the DNA strands of a gene. The mRNA is an RNA version of the gene that leaves the cell nucleus and moves to the cytoplasm where proteins are made. During protein synthesis, an organelle called a ribosome moves along the mRNA, reads its base sequence, and uses the genetic code to translate each three-base triplet, or codon, into its corresponding amino acid. 12 Inputs from the Ministry of Health and Family Welfare

advanced recombinant platforms like r-DNA, vector (Human or animal), m-RNA, etc. and therefore the starting materials like r-DNA13 host cell lines, plasmid construct, vectors, etc. along with various materials like filter bags/aid, media components, etc. to be used in upstream/downstream processing of COVID-19 vaccine manufacturing and the chemical/biological reagents, etc. used in, quality control testing needs to be made available along with the technology transfer.

3. Excipients (Adjuvants): Adjuvants and other excipients play an important role for manufacturing of COVID-19 vaccines as they are critical components to obtain strong immune response. Novel adjuvants which are patent protected have been used in manufacturing of COVID-19 vaccines like Matrix M1, CpG1018 which are monopolized and therefore the manufacturers should have access for the easy availability of these adjuvants like other ingredients for smooth manufacturing of COVID-19 vaccines.

4. Training: The training of the personnel working in manufacturing/Quality Control areas is very important benchmark for assessment of competency level in the manufacturing of COVID-19 Vaccine as a part of technology transfer.

Initiatives by Govt of India

Under the Mission COVID Suraksha, the Department of Biotechnology (DBT) is facilitating the augmentation of production capacities for Covaxin. Eforts are on to accelerate the technology transfer process for Covaxin production. Efforts are also underway to facilitate the supply of ‘master and working cell bank’ of characterized Vero cell lines for use in commercial production of the COVID-19 vaccine.

A Covid Drugs Management Cell (CDMC) has been constituted in the Department of Pharmaceuticals (DoP) to oversee and identify common concerns of the States with respect to drugs used in COVID-19 treatment. This involves coordination between MoHFW, DoP, NPPA and DCGI along with active engagement with States and UTs. 14In the latest budget, the Government of India has provided `35,000 crores for the Covid-19 vaccine and has committed to provide further funds, if required.

The strong foundations laid and the robust research and translation ecosystem generated through these initiatives have enabled the launch of an expeditious response against COVID-19 to overcome the unprecedented pandemic.

13 https://www.biologyonline.com/dictionary/deoxyribonucleic-acid Ribosomal DNA is the sequence of DNA that codes for ribosomal RNA. A nucleic acid refers to any of the group of complex compounds made up of linear chains of monomeric nucleotides. Each nucleotide component, in turn, is made up of phosphate group, sugar, and a nitrogenous base. Nucleic acids are involved in the preservation, replication, and expression of hereditary information. Two major types of nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). 14 https://www.indiabudget.gov.in/doc/Budget_Speech.pdf 6

Discussions on vaccine in Parliament

 The issue of Covid-19 vaccines were raised in the Parliament through debates and discussions and asking questions. The Hon’ble Members raised their concerns on all aspects pertaining to the covid-19 vaccines.

 The Hon’ble Speaker on behalf the House, congratulated the scientists and doctors on 5 February 2021, for their sincere efforts in making the indigenous COVID vaccine.

 The Standing committee on Chemicals & Fertilizers, presented its twenty- second report on ‘The status of Covid-19 Vaccine Production in India’, to the Lok Sabha on 17 March 2021. This report was laid in the Rajya Sabha on the same day.

The Way Forward

15 A way to ensure adequate supply and equitable and affordable distribution of vaccines, medicines and medical technologies, is to remove some of the barriers created by the intellectual property rights (IPRs), particularly in the area of technology transfer and to encourage manufacturers and research groups to work together towards a common goal. The IP waiver might open up space for production of Covid vaccines with emergency use authorisations (EUA) such as those developed by Pfizer, Moderna, Astra Zeneca, Novavax, Johnson & Johnson etc. on a larger scale in middle-income countries, also benefiting low income countries as the vaccine availability would increase.

India has already expressed support for waiver from certain provisions of the Trade Related aspects of Intellectual Property Rights (TRIPS) Agreement for the prevention, treatment and containment of Covid-19. The objective of the proposal is to ensure that the intellectual property rights do not become a barrier in rapid scaling up of manufacturing capacities throughout the globe to meet the objective of equitable, timely and affordable access for all to vaccines, therapeutics and other goods required to deal with COVID-19 pandemic.

Conclusion

COVID-19 is expected to usher significant attention towards the Indian vaccine market from investors, government, institutions and regulatory agencies. The emergence of newer

15 PMI WTO

7 technologies for vaccine development in areas such as genomics, structural and computational biology have enabled the development of novel vaccine development-and-manufacturing platforms that can be readily adapted to new pathogens. Organisations and Pharma companies conducting research on COVID-19 vaccines are expected to attract sizeable funding from investors. The influx of funding in the industry is expected to accelerate technological advancement and innovation.

The demand for contract manufacturing of vaccines is expected to continue mainly driven by global biotech companies with the aspiration to enter in the market, along with large pharmaceutical companies aiming to diversify their supply chain. The Indian vaccine manufacturers, with large production capacities and technical expertise, are expected to benefit from the growing popularity of the contract manufacturing of vaccines.