Why is it Difficult to Manufacture Vaccines for a Virus?

Vaccines are developed to reduce the risk of getting a disease. These help by working with our body’s natural defense mechanism to build protection. When a vaccine is induced into our body, the immune system responds and remembers in order to kill any infection that may strike in the future. Louis Pasteur realized the importance of external supplementary defense, thus, developed and administered the first successful vaccine against Rabies virus back in 1885.

Immunization is a chief aspect of primary health care. It is an indisputable human right as per WHO. When a vaccine is successfully developed, immunization becomes a global success story, helping save millions every year. At present, immunization prevents 2-3 million deaths each year from diseases like Tetanus, Influenza, Measles, Diptheria, and Pertussis. It is one of the best health investments too.

Although a lot of time and resources are poured into manufacturing a vaccine, it is critical in preventing and controllng infectious-disease outbreaks. Vaccine is an important tool in the war against anti-microbial resistance. Given the nature of viruses, development of vaccines can take months to years, which is bad news for most developing countries. Far too many people, including about 20 million infants, have insufficient access to vaccines each year.

Types of Vaccines

When creating a vaccine, several important parameters are considered:

• How our immune system responds to the microbe
• Who needs vaccination against the microbe
• Best technology or approach to create the vaccines

Each type of vaccine developed is designed to teach our immune system how to fight off various kinds of micro-organisms, and prevent any serious diseases they might cause. On the basis of the above mentioned factors, a vaccine is developed as one of the following:

1. Live-attenuated Vaccines: These use a weakened (or attenuated) form of the microbe that cause a disease. Such vaccines are similar to the actual infection that they help prevent, so they create a strong and long-lasting immune response. Just one or two doses can provide a lifetime protection. These vaccines are used to protect against Measles, Mumps, Rubella (MMR), Chickenpox, Yellow Fever, Rotavirus, Smallpox.

2. Inactivated Vaccines: These use killed version of the microbe. The immunity provided by these are not as strong as live vaccines. So, we may need several doses or booster shots over time to imbibe an ongoing immunity against diseases. These are used for Hepatitis A, Polio, Rabies, Flu.

3. Subunit, recombinant, polysaccharide, and conjugate Vaccines: These type of vaccines use specific parts of the microbe, e.g. protein, capsid (a casing around the germ), or sugar to provide a very strong immune response that targets its key parts. Booster shots might be required for ongoing protection. These vaccines are used to protect against Hepatitis B, HPV (Human Papilloma Virus), Shingles, Pneumococcal disease, Meningococcal disease, Hib disease (Haemophilus Influenza Type B), Whooping Cough.

4. Toxoid Vaccines: These vaccines use a toxin made by the microbe, creating immunity to parts of the germ that causes disease instead of the pathogen itself. Immune response is targeted to that toxin as opposed to the microbe itself. These vaccines protect against Tetanus, Diptheria.

Apart from these major type of vaccines, scientists are continuing researches to further develop DNA vaccines and recombinant vector vaccines (also called platform-based vaccines). The former is easy, inexpensive and produces long-lasting, strong immunity while the latter acts like the natural infection and helps teach the immune system to fight off germs.

Although it takes about 10-15 years to develop a vaccine with almost no side-effects, scientists are working towards reducing time lag between incidence of infectious disease and development of vaccine. With improved technology and advances in molecular and genetic research, vaccine researchers are striving to decrease this time span and help people acquire their desired immunity thus, saving lives.

Some vaccines that have been developed for infectious diseases are listed in the table below:

S.No.	Name of Disease	Name of Vaccine	Vaccine Type	Year Developed
1.	Polio	IPV, OPV	Inactivated	1955, 1961
2.	Diptheria	DT, DTaP, Td, Tdap	Toxoid	1921
3.	Hepatitis B	Recombivax HB, Energix-B	Recombinant	1981
4.	MMR	MMR, MMRV	Live-attenuated	1971
5.	Influenza	IIV, RIV4, LAIV4	Inactivated, Live-attenuated	1930s
6.	Pertussis	DTaP, Tdap	Whole-cell (Inactivated sub-unit)	1914
7.	HPV	Gardasil® 9, 9vHPV; Gardasil®, 4vHPV, Cervarix®, 2vHPV	Recombinant	2006
8.	Rotavirus	RotaTeq® (RV5), Rotarix® (RV1)	Live-attenuated	2006
9.	Tetanus	DT, DTaP, Td, Tdap	Toxoid	1924
10.	Varicella	Varivax®, ProQuad®	Attenuated	1970s
11.	Pneumococcal	PCV13, PPSV23	Conjugate, Polysaccharide	1980s
12.	Anthrax	BioThrax®	Inactivated	1930s
13.	Rabies	HDCV, PCEC	Inactivated	1964

Development of Vaccines

You have to understand the structure of the microbe because to create a vaccine you need to know enough about the infection to be able to mimic it. A vaccine is essentially a mimicked infection.

Professor Adam Finn, head of Bristol Children’s Vaccine Center (BCVC) research group, and David Gaum Professor of Paediatrics at the University of Bristol, UK

Thus, each vaccine has to go through a rigorous series of clinical trials passing which, it is made available to the public. Before going for bulk manufacture, the vaccine has to be screened multiple times. Even after the vaccine is delivered, researchers and scientists have to be on the lookout for any adverse reactions in the general population.

Vaccine Trials, Immune Response, and Risk

A series of studies is done using cell cultures and animal models so that doctors and researchers can test vaccine safety and induction of an immune response. Before anything is given to humans, careful steps are to be taken, making sure all material is manufactered in a completely safe and controlled way. This is done to know exactly what it is that is going to be given to people. No contamination is the main goal to be achieved. This is the pre-clinical research part.

After pre-clinical research, if results are found to be positive, the vaccine is tested in a small group of people. As small as half a dozen. This is called Phase I clinical study. This test helps doctors rule out major safety issues and work out the right dose for the next step in the testing process.

Phase II involves giving the vaccine to a larger number of people, often 100 or 200. It can go as high as 1000. This trial tests whether the vaccinee provides a consistent immune repsonse with researchers looking out for any side effects that might occur.

Phase III trials are conducted to test the vaccine’s protection against a natural infection, when the disease is reasonably common. These studies include tens of thousands of healthy volunteers so doctors have a good chance of discovering rare problems that don’t show up in Phase II trials. The third phase proves that the vaccine prevents disease.

After the vaccine is approved, it is made available to the public. Either a funded national immunization program or private purchase makes the vaccine accessible to all. Monitoring continues, even then, as part of Phase IV trials. Here doctors are encouraged to report any unexpected apparent side-effects.

Are any Coronavirus Vaccines Developed Till Now?

Numerous institutes and pharmceutical companies are in the process of creating the best, most efficient coronavirus vaccine. As of 23^rd July 2020, major candidates found to be the front runners in this marathon to cure Covid-19 are listed below:

S.No.	Candidate	Sponsor	Trial Phase
1.	Inactivated vaccine	Wuhan Institute of Biological Products; China National Pharmaceutical Group	Phase III
2.	CoronaVac	Sinovac	Phase III
3.	Bacillus Calmette-Guerin (BCG) live-attenuated vaccine	University of Melbourne and Murdoch Children’s Research Institute; Radbound University Medical Center; Faustman Lab at Massachusetts General Hospital	Phase II/III
4.	AZD1222	The University of Oxford; AstraZeneca; IQVIA	Phase II/III
5.	mRNA-1273	Moderna	Phase II
6.	Ad5-nCoV	CanSino Biologicals	Phase II

Let us hope a suitable and effective vaccine completes all trials soon so that the world may be free of the pandemic.