Vital Vaccines

Have you wondered how COVID-19 vaccines were developed so rapidly ?

The normal period of time for manufacturing a vaccine takes 12 years in total, 8 years to research the pathogen, and another 3-4 years of trial, error and production. Earlier, the vaccine development involved a series of steps, but in the case of the Corona-Virus Vaccine, the field of computational biology and international cooperation helped the biologists, computer scientists and the regulators accelerate the whole process without compromises on any protocols and any step. The government's ultimate plan is to resume normal activities after at least 75% of the population has been vaccinated with the current vaccines. In the next 3 years, when the Covid virus has mutated multiple times, with multiple variants, a “polyvalent vaccine” will be supplied. With the buzz of compulsory universal Vaccination all around, let us first understand the basic biology of vaccines. 

History :

The first vaccine was manufactured in 1000AD in China, using a method of nasal insufflation, administered by blowing powdered smallpox material (usually scabs) up the nostril. In the 1720’s, a variation experiment with six prisoners in Newgate prison in London proved successful and began gaining popularity, although the British prince died due to variolation. Edward Jenner in the early 1800’s rose to fame for his famous cowpox based vaccinated experiment for smallpox vaccine.

Chickenpox and smallpox, both these diseases are caused by the same virus strain, the Variola Virus, while cowpox is caused by the Vaccinia virus, which is much milder, and hence used in the Vaccine. Thus vaccines get their name from this Vaccinia Virus, which did not cause many side effects and was easy to culture. 

Mechanism of Vaccine Action:

Classical vaccines are mainly divided into Live/Attenuated, Inactive/killed, Toxoids, Viral Vector, RNA vaccines or Conjugate vaccines. These types of vaccines operate on two primary principles. The first one is using a weakened pathogen. The infectivity of the severity of the diseases is reduced through changes in the pathogen and is given as vaccines which also require lesser load per dose. The pathogen is weakened by being passed through animal or human cells until it picks up mutations that make it less able to cause diseases. The second method is killing the pathogen, where the virus is usually rendered uninfectious using chemicals(toxoids), such as formaldehyde or heat, like the Tetanus and Diphtheria vaccines. Additionally, there are subunit vaccines which use just a part of the pathogen to confer immunity. 

Effectiveness of a Vaccine : 

Each vaccine targets a variant of the pathogen, which are the different proteins or amino acid structures.  A monovalent vaccine, using only one variant of the antigen, is less effective than a polyvalent vaccine which uses more than one variant, or whole antigens/pathogens(like the Pneumovax 23 vaccine for pneumococcal bacteria as it contains contains antigens for different variants of coccus bacteria which infect humans).

The COVID vaccine was a monovalent vaccine, and this property is one of the reasons it took such a short time to manufacture. A vaccine’s valency is directly proportional to its effectiveness.

Constituents of a Vaccine dose:

The newer vaccines contain Toll Like Receptor activating components as adjuvants -such as TLR7, TLR8 and TLR9 - to improve a vaccines function. Toll Like Receptors are a signalling mechanism or sensors on the top of cells that sense the presence of DNA, RNA or nucleoids inside/outside around cells and see it as a threat. This activates the DNAses and alerts T and B cells or directly produces an enzyme to kill it. Secondly, a vaccine also contains preservatives like Thiomersal to protect vaccines from bacterial infections and avoid other foreign pathogens from getting inside. Thirdly, vaccines also contain excipients which stabilise the vaccine during manufacturing and storage processes .There is a buffer(like salt), which differs in type and concentration, a chemical to stabilise pathogen particles, attenuated or inactivated, and makes them get attached to the Toll Like Receptors. Additionally, it has a stabilizer that keeps particles alive when it is exposed to heat/cold/radiation by absorbing it. Vaccines contain a surfactant which gives a layer of protection to the pathogen to prevent self destruction. In addition, it is important to note that vaccines also contain a suitable pH range - to keep the antigen particles alive. 

Methods of Delivery :

The common routes of vaccine administration can be Needle or microneedle injection, given subcutaneously or intramuscular. Vaccines like the polio vaccine, rotavirus vaccine and typhoid vaccine are oral ones, which are very desirable but difficult to produce. Vaccines can also be liposomal and nanoparticle-based, which are slow-release delivery systems. For animal vaccines, the preferred modes of administration is intra nasal or ocular, not in humans.

Advantages and Disadvantages of Classical Vaccines :

They are time tested, and the pathogens have predictable characteristics, hence we don't have to worry about new strains of mutation. However it is also considered unsafe due to cases of reactivation of the pathogen. These vaccines have established protocols for preparation and entailed very few patents or IP based barriers involved in its production, as they have been in the pharmacopoeia for a while. Yet, a very high setup of BIO SAFETY LEVEL 3 is needed, which is expensive.  

Egg based Vaccine Mechanism: 

Taking the Flu virus vaccine as an example, this strain under the latest circulation is obtained by companies from the governments’ network of institutes who search for new viruses every season. Next comes reducing the virulence of the virus, by either making it weak by changing its Codon bias (the exon that DNA codes) or inactivating it by using chemicals. Next is the growth stage, where the Flu viruses are injected into fertilized, live chicken eggs and are incubated for several days. The last step is filling, whose requirements change with each type of vaccine. This is the easiest and least time consuming step but often poses a serious bottleneck in the production process. Flu vaccines were not very efficient themselves as some viruses grew poorly in eggs and were difficult to get a good dose out of. Additionally, there were allergies and the variants of the virus are difficult to address. A pre planned vaccine stock has to be created since an epidemic or pandemic might hamper the production process and a polyvalent vaccine is expensive to produce under emergency conditions. The Yellow Fever vaccine as well had disadvantages as they were administered without an allergy test and allergies to egg proteins were commonly found. Additionally, live virus vaccine developments like these are extremely R and D( Research and development) intensive processes. 

Cell-Based Vaccines:

In the 1960’s, the availability of commercial cell culture growth media increased and several types of cell-based vaccine developments started. Monkey Kidney Epithelial Cells (VERO cells) are immortalized by inducing various pathways in the cell. These cells continue to divide like cancer cells and hence produce a continuous supply of cells and ultimately vaccine production can be maintained. However, their disadvantages are that the cost of raw materials like Media, Serum etc is very high and the setup costs of a sterile production plant itself is very high. Diplomacy of political relations also interferes with cell based vaccines production as essential raw materials like media and serum are produced only by developed countries, and other underdeveloped or developed countries heavily rely on them for its supply. Additionally, under emergency times like a pandemic, the production time of 11-12 years is not sufficient to meet the high demands. 

Difference between Egg and Animal Cell vaccines:

There is 22 vs 11 week time of production for egg based and cell based vaccines respectively.

No allergic materials are found for cell based vaccines as animal cells are used. Animal cell vaccines have a high production capacity as the virus propagates easily and in good amounts within the animal cells, while egg based vaccine production needs a lot of eggs, which cannot be acquired easily. Cell systems are also easily manageable and confer better production against the circulating real pathogens in the body than the egg vaccines. 

The INDIAN COVID Vaccine:

The method of production for these vaccines is as follows: The SARS CoV2 viruses are first propagated in the African green money, VERO cell lines. This is followed by extraction of the active viruses. Next, agents like Beta-Propiolactone and Formalin inactivate the pathogen. The COVAXIN contains inactivated SARS CoV2 along with other inactive ingredients like Aluminium Hydroxide, TLR7/8 and activators like Imadazoquinollnone, Phenoxyethanol and PBS. Since Covid viruses are produced in a production facility, a Biosafety Level 3 environment is required.