Vaccines- the what and how?

Updated: Nov 23, 2020

By Gayatri Muthukrishnan, Ph.D and Sanjana Rao, Ph.D


(The information in this article is relevant as of 23rd November, 2020)


While the whole world is waiting with bated breath for a Covid-19 vaccine, we thought we would take a step back and explain to our readers about the basics of vaccines, the different types and the testing process.


What are vaccines?


Vaccines are biological substances which help the body fight infections that they have never come in contact with before. It helps build the defence system or the immunity of the body. While some vaccines help to prevent the onset of infectious diseases (such as Measles) there are others which have a therapeutic function (such as vaccines against HIV or Cancer).


In most cases, vaccines contain the whole pathogen (inactivated or attenuated) or parts of the pathogen, so that the body develops the required defence (antibodies, T-cells) to protect itself from the disease causing organism when infected.


Type of vaccines


There are different types of vaccines broadly characterized as Whole pathogen vaccines, Subunit vaccines and Nucleic acid vaccines.


Whole pathogen vaccines:

Live-Attenuated vaccines: This kind of vaccine contains bacteria or viruses that have been weakened under laboratory conditions. These bacteria or viruses are not capable of causing diseases and their main goal is to boost a defense or immune reaction in our bodies to protect us against infections such as Tuberculosis, Chicken-pox or Polio.


Inactivated vaccines: This kind of vaccine contains viruses or bacteria that have been destroyed by chemical or physical processes and do not contain any living organisms and hence do not cause the disease. For e.g., Typhoid vaccine and Polio vaccine.


Subunit vaccines

Instead of whole cells, these vaccines contain parts of the virus or bacteria (an antigen) that stimulate the body to develop an antibody, a protective protein produced by the body in response to an antigen. There are different kinds of subunit vaccines such as


Conjugate vaccines often contain the polysaccharide (sugar on bacteria surface) conjugated to a protein antigen - together they induce better immunity response. E.g. Haemophilus influenzae type B (Hib) vaccine.


Toxoid vaccines are usually developed against toxins released by illness-causing bacteria like Diphtheria and Tetanus. These are chemically inactivated toxins, known as toxoids.


Recombinant vaccines - Here, cells like yeast or bacteria are used as factories to produce large amounts of the viral protein subunit by introducing the viral DNA in these cells. The proteins collected from these cells form the active ingredient in the vaccine. E.g. HPV vaccine.


Nucleic acid vaccines

The most recent technology in vaccine development is introducing genetic material that gives rise to the antigen for which immune response is sought. This can either be a DNA vaccine or RNA vaccines.


Instead of introducing the genetic material directly, another approach is to use a carrier. For eg., the DNA or RNA is introduced into a different harmless, non-replicating viral vector.



Clinical trial for vaccines


Before a vaccine is ready to be administered to humans, it has to go through a rigorous process of testing which is called a clinical trial. Vaccine development typically consists of a Discovery or Preclinical Phase followed by Phase I-Phase III clinical trials after which a vaccine is either approved and large scale production and manufacturing can be carried out or further testing needs to be carried out.


Discovery and Preclinical studies involve the laboratory research that goes into designing the vaccine target, testing it on cells and tissues and further testing it in animals to check if it elicits an immune response and safety. This phase usually lasts for 2-5 years. In Phase I (also called first-in-man study), the vaccine is tested on a small number of healthy volunteers to test if the vaccine produces an immune response and is safe to be administered. In Phase II, hundreds to thousands of patients are recruited at multiple sites or locations in order to conclude that the vaccine is safe, produces a robust immune response and can help prevent the disease. Usually here people of different ages and health status are tested. After this, a Phase III trial is conducted, which is essential in order to register the vaccine for approval before launching the vaccine in the market.




In Phase III (and sometimes Phase II), thousands of people are recruited and there is usually a comparison between people who are given the vaccine and people who are given a placebo (a person who receives the control vaccine) to make sure that the vaccine is safe and effective. Here the groups who receive the vaccine are also randomized and the clinical trial is either performed as a single-blind(where the participants do not know if they have received the vaccine or the placebo) or double-blind (where the participants and the researchers do not know who gets the placebo and who gets the actual vaccine) to check if the effect that is seen is due to the administration of the vaccine and not due to other factors and to reduce the bias that is inherent to the clinical trial. If Phase III is successful, the data from the clinical trial is then submitted for approval to the regulatory bodies, agencies like the FDA in the US, or EMEA in the EU.


Phase IV is conducted once a vaccine is already in the market and to ascertain the long-term effects of a vaccine in different populations and to make sure that the vaccine works under real world situations. This is the step when post-market surveillance of the vaccine is done.


Vaccine manufacturing and production


Normally it takes anywhere between 6-36 months to manufacture a vaccine and make it ready for distribution. 70% of this time is dedicated to quality testing and control of the vaccine. All the components, reagents and manufacturing processes have to be for Good Manufacturing Practices (GMP), which are minimum requirements that a manufacturer must meet to assure that their products are consistently high in quality, from batch to batch, for their intended use. The manufacturing process depends on the type of vaccine that needs to be produced.



Vaccines against Sars-Cov-2


There are more than 165 vaccines that are in different stages of development. It is good to remember that due to the speeding up of vaccine development and clinical trials, even with short term positive results, long term efficacy and effects are hard to validate, so having many different vaccines in the pipeline is important.


Below, we have listed those that are in Phase III trials or being developed in India.


There are two inactivated vaccines in Phase III trials. One is a state-owned Chinese firm, Sinopharm and secondly, a China based private firm, Sinovac Biotech (CoronaVac).


Indian company Bharat Biotech, in collaboration with Indian Council of Medical Research and National Institute of Virology have developed an inactivated vaccine, Covaxin. They are currently in the Phase I/II combined trial.


A second Indian company, Zydus Cadila, based in Ahmedabad, has developed a DNA vaccine that has been approved to begin Phase I clinical trials as of July 3rd, 2020.


Currently there are two mRNA based vaccines against Sars-Cov-2 that are in Phase III trials. One is US-based, Moderna in partnership with NIH and the second is a German company, BioNTech in collaboration with Pfizer, based in New York, and the Chinese drug maker Fosun Pharma.


AstraZeneca along with University of Oxford have developed a non-replicating viral vector vaccine. Here they introduce DNA against the Sars-Cov-2 spike protein in a Chimpanzee adenovirus. Hence, the vaccine is termed ChAdOx1 nCoV-19. They have started Phase III trials.


In order to speed up the clinical trial process for Covid-19 and reduce the time, sometimes the clinical trial phases can be combined or Phase III is initiated while Phase II is going on provided the safety standards have been met. There is also something called a challenge trial which has been initiated for Covid-19 in which the virus is purposefully given to patients registered in the clinical trial who have been given the control or test vaccine.


All of us are affected by the pandemic and often wonder why despite the global effort the vaccine is not ready yet. One must understand that there is a need to make sure that the vaccine goes through the most stringent testing process to not only ensure that it works but also ascertain if it is safe for the general population.


*Vaccine update

September 8th, 2020: The Oxford vaccine trial is paused as Phase III as one individual has an adverse effect. It is not yet known whether the reaction was directly caused by the company’s vaccine or was coincidental.

The pause will allow AstraZeneca, a British-Swedish company, to conduct a safety review and investigate whether the vaccine caused the illness.

September 14th, 2020: The Oxford vaccine trails were resumed in the UK and globally resumed on October 23rd, 2020. The restarting of the trial shows that the event was judged not to be vaccine related.

23rd November, 2020: On November 16, Moderna announced that its phase three study shows the vaccine is 94.5 percent effective in preventing COVID-19—including severe cases of the disease—without any significant safety concerns. The company also said its vaccine can be safely stored on ice or in a normal refrigerator for 30 days. Pfizer found their candidate to be 95 percent effective in preventing mild and serious cases of COVID-19—and 94 percent effective in adults over 65 years old—with no serious safety concerns.On November, 20th, Pfizer has applied to the FDA to approve its vaccine for emergency use. Moderna is expected to follow suite by the end of the week.

The Oxford vaccine has been found to be give 70% protection, but the researchers say the number could change to 90% if the dosage is adjusted.




References


General vaccine information

https://vk.ovg.ox.ac.uk/vk/types-of-vaccine

https://www.niaid.nih.gov/research/vaccine-types


Vaccine trials links

The clinical development process for a novel preventive vaccine: An overview

Can vaccine clinical trials be sped up safely for COVID-19?

https://en.wikipedia.org/wiki/Vaccine_trial#Phase_One_Trials

What you need to know about the COVID-19 vaccine

How long does it take to develop a vaccine?

How are vaccines produced?

Placebo use in vaccine trials: Recommendations of a WHO expert panel


Site to track Sars-Cov-2 vaccine

https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html


Latest published articles on some of the vaccines

Moderna vaccine (July 14, 2020) -

https://www.nejm.org/doi/full/10.1056/NEJMoa2022483

Oxford vaccine (July 20, 2020) -

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31604-4/fulltext

https://timesofindia.indiatimes.com/india/coronabytes?from=mdr

https://www.nytimes.com/2020/09/08/health/coronavirus-astrazeneca-vaccine-safety.html

https://www.bbc.com/news/health-55040635

https://www.nature.com/articles/d41586-020-03326-w


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