VACCINATION

 

VACCINATION

In today’s world vaccination is the cheapest and easiest method of protection against potentially lethal infections. Back in 1796, English doctor Edward Jenner used cowpox blood serum to generate immunity to smallpox. In the late 1800s, Louis Pasteur showed that microbes cause several infectious diseases. Later, Pasteur developed the process of laboratory-created vaccines using microbes. Vaccine development, testing and regulation are a tedious and complex process, often lasting several years and involving combined efforts of public and private institutions.

 

The World Health Organization (WHO) provides essential guidance to respective National Regulatory Agencies (NRAs), vaccine manufacturers, scientific investigators and clinicians involved with the clinical assessment of candidate vaccines (WHO Technical Report Series No. 850, Annexure 3, 1995). The vaccine Research and development (R&D) activities for new vaccines involve mainly three stages: developmental, granting of license and post-licensure surveillance. The initial developmental stage consists of two phases: pre-clinical R&D and clinical R&D. WHO manual on ‘Immunisation in Practice’ describes the basic standards of vaccine storage, transportation, suitable injection techniques for vaccine delivery, and safety of injections.

 

Vaccines versus drugs:

 Vaccines are essentially preventive agents and not curative. Vaccines stimulate a person’s immune system to produce immunity to a specific disease and protect the person from that disease. Vaccines are mostly specific to a particular microbe (virus or bacteria) and helps in tuning the recipient’s immune system against it. Following immunisation, vaccines elicit a controlled and very specific immune response and create cellular memory of immune cells to protect the person from future infection by the same infectious agent. In most cases, vaccination is required once in a life-time and may involve booster doses in some diseases like tetanus, polio, etc. Vaccines are generally administrated orally, through nasal spray or injection and do not require to be metabolized. On the contrary, prescribed medicines or drugs are chemical, herbal or biological products often used as curative agents and/or protective agents. Unlike vaccines, drugs are frequently prescribed following diagnosis of a disease and may require to be administrated several times for complete cure. Drugs are composed of active ingredients which in most cases may be chemically synthesised (like paracetamol), natural (like penicillin), and biological/biologics (monoclonal antibodies such as rituximab). Unlike vaccines, drugs essentially require to get metabolised and absorbed to become active inside the body. After metabolism and action on specific substrate, drugs get cleared from the person’s body through excretion (urine and/or stool).

 

Vaccine testing and the approval process

The Centres for Chronic Disease Control and Prevention (CDC), USA has categorised the various stages in the development of a vaccine, such as initial investigative stage, pre-clinical stage, clinical development, regulatory review and approval, manufacturing, and quality control surveillance. The ‘pre-clinical assessment stage’ of a vaccine candidate is an initial testing phase that lays the foundation of subsequent clinical trials. In pre-clinical stage testing, laboratory-based molecular techniques are used, followed by animal trials. In this phase, either a novel vaccine or a new combination of vaccines is evaluated. The immunisation of animals with candidate vaccine preparations and the resulting immunogenicity data derived from these animal models provide valuable data to select the product doses, schedules and routes of administration which are evaluated further in clinical trials. Immunogenicity is defined as the “capacity of a vaccine to induce antibody mediated and/or cell-mediated immunity and/or immunological memory” (WHO Expert Committee on Biological Standardisation). The next stage - ‘clinical development’ - is a three-phase process comprising of Phases I to III. Phase I clinical studies, also referred as human trial, involves the first administration of a candidate vaccine to humans in small numbers (like 20 to 100 volunteers), to test the properties of a vaccine (Does this vaccine seem to work?), safety (Is this vaccine safe?), tolerability (Are there any serious side effects?), and clinical laboratory and pharmacological parameters (How is the size of the dose related to side effects?). Phase II studies engage several hundreds to thousands of subjects from the target or at-risk population at several places to obtain primary evidences on a vaccine’s ability to produce its desired effect in protecting against the disease/ infection in the target population (How are the volunteer’s immune system responding to the vaccine candidate?) and general safety (What are the most common short-term side effects in the subjects?). The Phase III clinical trials involve thousands of volunteers to assess the protective efficacy (Is the vaccine safe and effective?), safety profile (What are the most common side effects?). Further, it is important to measure the vaccine’s effectiveness by comparing the persons who got the vaccine and those who did not. An application by the manufactures based on the vaccine’s clinical development data for a market authorisation is submitted to the concerned NRA in that particular country. Following approval by regulatory authorities, potent vaccine becomes available in the national or international market. After the grant of license, vaccines may also undergo Phase IV formal studies, referred as postmarketing studies or post-marketing surveillance (PMS).

 

National Vaccine Policy (India)

Following the recommendation of National Technical Advisory Group on Immunisation (NTAGI), The National Vaccine Policy Document (India) was developed in 2011. This Document defines the broad issues of strengthening the R&D of vaccines, introduction of new vaccines under the Universal Immunization Program (UIP), operational efficiency of UIP, and implementation and monitoring. It also addresses issues related to vaccine security and vaccination programs of National Health Policy in India.

 

Ethical considerations

 Strict ethical norms are associated with vaccine research as it involves sacrifice, experimental harm, pain and discomfort of a large number of laboratory animals and risking health of human subjects. Mammalian model animals such as rats, mice, rabbits, pigs, calves, cattle, sheep, monkeys, and horses are frequently used for vaccine research to assess: (i) vaccine safety, (ii) protection against the disease/infection, (iii) limiting clinical symptoms, (iv) critical function of immune system, (v) magnitude of immune response, (vi) routes of administration, and (vii) which immune components are induced. Major objective of ethical considerations for clinical trials include rationale of the trial, selection of participants, limiting biasness, health outcome, participant’s consent, confidentiality, medical care and clinical follow-up. Respective “Institutional Ethics Committees” (IEC) and Indian Council of Medical Research (ICMR) oversee the strict ethical compliance as per the guidelines issued by ICMR, New Delhi.

 

Current perspective

More than 20 billion vaccine doses are produced globally every year, of which nearly 3 billion doses are produced in India. Under the current COVID-19 pandemic, 143 candidate vaccines are under pre-clinical evaluation and 33 are undergoing clinical trials (WHO Report as of 28 August). Two Indian vaccines namely, Covaxin (inactivated whole virus) by Bharat Biotech and ZyCoV-D (DNA plasmid vaccine) by Cadila Healthcare Ltd are under Phase I clinical trial. Serum Institute of India in collaboration with Codagenix, USA developed another candidate vaccine which is still under pre-clinical trial