Vaccinations, The Journey So Far and The Road Ahead

The advancement of science has led to the development of vaccines that arm the human beings against infectious diseases, reducing morbidity and mortality. Vaccines are the monetarily convenient mass scale preventive measure against deadly diseases and pandemics. The constant scientific efforts in this area has led to new and better ways of conferring immunity to mankind to the disease that have created havoc in the past. This is review of the different types of vaccination techniques that have developed over time and how these have been utilised to address the SARS-CoV-2 virus. The future for immunization is promising with vaccinations being developed for diseases like cancer.


Introduction
Vaccination treatment empowers the body's immune system against the harmful foreign intruding elements, the pathogens.
When the body is introduced, on purpose, to the weakened version or any kind of blueprint of the specific antigen in the pathogen, it produces antibodies against the antigen. The primary response being antigen specific antibody production, the body also produces memory cells that remain alive even after the antigen is defeated.
In the event of infection by the real antigen, the body responds quickly with the memory cells producing the antibodies effectively [1]. The doses of vaccines required, are case specific and depend on what is required to ensure long term development of memory cells and antibodies.
The agents that can be introduced to activate body's immune response have developed historically. The earliest vaccine developed by Edward Jenner against smallpox was the first live attenuated vaccine [2]. These kinds of vaccines have been further developed against other diseases like measles, mumps, rubella etc. Live viruses that have been attenuated such that they can't cause the disease but still can replicate, even if not properly, in the human host, can be recognized by the human immune system. Their effect being very similar to the actual natural infection, these vaccines incite long term immune response, even conferring lifetime immunity. However, there always remains the risk that weakened virus can gain back the virulence through mutations while being inside the human body, which was reported in case of the oral polio vaccine (OPV). This is the main reason OPV was banned in the USA in 2000 [3]. Caution also needs to be exercised with such vaccines for people with weak immune system such HIV patients. These live vaccines need to be stored at low temperatures and thus easy and ample access to refrigeration process is essential for widescale vaccination program using attenuated vaccines. These factors affect the potential of any live attenuated vaccine to be able to address the current SARS-CoV-2 virus, which itself has undergone numerous mutations for its survival gaining further lethality and contagiousness with each mutation.
Inactivated form of harmful foreign elements, when introduced into the body can still incite immune response. Virus or bacteria killed using heat or chemicals e.g. formaldehyde or other means like Ultraviolet rays are the candidates for inactivated vaccines.
These can be conveniently stored and the risk of the introduced antigen gaining back pathogenicity is also avoided. However, these are not as efficacious as the live attenuated vaccines and multiple doses may be required to confer immunity. Currently the Sinovac

vaccine developed against the Covid-19 virus in China by Sinovac
Biotech is based on inactive particles of SARS-CoV-2 virus [4].
Covaxin developed by Bharat Biotech in India is also inactivated vaccine against SARS-CoV-2 [5].
Vaccines are also developed based on a part of the pathogen: a protein or carbohydrate or the antigen itself, which when injected into the body trigger immune response. These are referred to as Subunit vaccines [6]. These are more safe as only a part of the whole germ is introduced and are expectedly easy to produce. Conjugate vaccines are developed against those foreign elements whose antigens can't be recognized by the body's immune system as they remain encapsulated in polysaccharide capsule [9]. Strategically an antigen from another identifiable pathogen is coated in the same polysaccharide capsule to enable the immune system to recognize the polysaccharide coating as threatening and to attack the same. Haemophilus influenzae type b (Hib) was successfully eradicated using conjugate vaccine technique [10].

Conjugate vaccine against SARS-CoV-2 is being developed in Cuba.
It comprises two doses: The Spike protein of the SARS-COV-2 virus and tetanus toxoid conjugated to it [11].
Toxoid vaccines are also widely used to induce immunity against the toxin that is released by the foreign element i.e. the germ. The body acts against the toxin and not the entire germ and thus chances of single dose leading to lifelong immunity is low [12].
Methods by which the antigen instead of being externally administered into the body are produced within the body, have been developed, to induce immunity. The antigens are delivered into the body a 'vector', which is generally a virus that has either been engineered to be incapable of replicating inside the body and causing any disease and capable of undergoing degradation or is capable of replicating but is weakened to be able to cause any disease [14]. One such virus that qualifies for acting like a vector is the Adenovirus belonging to the family Adenoviridae [15]. There are different genera in the family that infect mammalian species, birds, reptiles, amphibians and fishes. These are naked, viruses with double stranded DNA genome. Adenovirus generally causes common cold in humans but can be dangerous for human beings with decreased inherent immunity.
The commonly occurring adenovirus infections in humans make the body already immune to these as antibodies against the virus are expected to be already present in the body. This can affect the potential of this virus to act as a vector for carrying DNA of specific antigen. This issue is overcome by using adenovirus from other species that the human body has not likely encountered.
There are numerous vaccines that have been developed against the SARS-CoV-2 by this method. The adenovirus vector is designed to encode for the spike protein inside the body to elicit immune response against the Covid-19 virus. The AstraZeneca-University of Oxford vaccine uses the engineered version of Chimpanzee Adenovirus ChADOx1 as vector [16]. Johnson & Johnson uses its proprietary recombinant adenovirus that was being developed against the Ebola virus as the vector [17]. Sputnik V from Russia uses recombinant human adenovirus [18], so does CanSino [19] from China.
The most recent approach in vaccine development is that based on nucleic acids. Similar to the viral vector process, the mRNA with restricted to foreign pathogens but has also advanced to the field of treatment of cancer [23]. The process to stimulate body's own immune system to act against the cancer cells is being developed.
Therapeutic vaccines are based on personalized precision therapy whereby patient's own white blood cells are taken from the body and engineered upon e.g. in case of prostate cancer, the white blood cells are mixed with prostatic acid phosphatase (PAP) and then reintroduced into the patient through infusion [24]. This has allowed patients to live longer. Drugs that inhibit the various check point inhibitors e.g. Keytruda acting against PD-1 inhibitor, boosts the body's own immune response against prostate cancer cells [25,26]. The vaccine against the Human papillomavirus (HPV) helps prevent cervical cancer and other types of cancer linked to it [27].

Biographical Notes
Dr Sarbani Chattopadhyay PhD, LL.M., is a computational biologist with a PhD in Biochemistry from the University of Calcutta (India) and a LL.M. in European IP and IT Law from the Georg-August-University of Göttingen (Germany). She assists her clients in searching and analysing patents to gain insights about patent portfolios and technologies.