Vaccines 101

What is a Vaccine?

Vaccine, a name coined by Edward Jenner after he successfully came up with the first-ever vaccine for smallpox, is anything that primes our immune system against a particular disease. 

The aim is to get our immune system to make antibodies against the pathogen, when we are actually at the risk from the infection, by introducing it earlier in lower, controlled amount. This is done in several ways, by inactivating and injecting the actual virus/bacteria, introducing dead-virus/bacteria, just parts (a few proteins) of the virus instead of the whole organism, DNA/RNA of the virus (more about how this works at the end of the article) and many more! This image below from HIV Vaccines Trial Networks gives us an idea of the different types of vaccines using HIV as an example. (Please note, no successful vaccine exists for this till date!)

 

source: https://www.hvtn.org/en/science/hiv-vaccine-basics/types-vaccines.html

What are the steps involved in Vaccine Development?

According to the Centre for Disease Control and Prevention, United States there are six pit stops in the race towards a vaccine. [1] These are: 

 

Exploration: 

The first stage of vaccine development starts in the laboratory. Researchers culture pathogens in the lab and decide which method out of the several mentioned above is best suited for the infection at hand. Then they work to optimise the method and then test it.

Pre-clinical Testing:

This is the first round of testing out of many more to follow, where researchers test out their vaccines in tissue or cell cultures and in model animals to see if they provide immunity as hypothesised.  It is noted that several vaccines don’t cross this milestone by failing to produce immunity or by being harmful to the test subjects.

Clinical Development:

This is the infamous clinical trial phase where many new drugs are currently parked, waiting for approval. The Clinical trials have three phases where the vaccines are administered to groups with varying numbers of people over specific periods of time. 

 

At present, the developments in biotechnology have enabled the previous two phases to be completed in the order of several months. This phase is one of the major contributors to the long time-tag associated with vaccine development.

 

Phase I

In the first phase, the rules are simple. A small group of healthy individuals is chosen and administered the candidate vaccine. If, after a sufficient period of time, they are safe and have not developed any side effects because of the vaccine, it means we have cleared level 1. 

Phase II

As expected, level 2 has more tasks that need to be completed before we can progress. Here, hundreds of human test subjects are chosen but this time we are looking for more information. We now want to know all the details. We are looking at how much ‘immune response’ is caused in the body when this drug is introduced (A.K.A. Immunogenicity), how frequently the vaccine must be administered and the dosage to be given.

Sorry! You don’t level up until you have found that perfect combination! 

Phase III 

Like how in those few video games, the final level is a recap of all the tasks done from the beginning but with more experienced opponents (I know an End-Sem might have been a simpler analogy, but I really don’t want to think about that right now. Do you?), in this phase we scale up to include thousands or tens of thousands of test subjects and measure how safe and effective the vaccine is. Simply put, we just want to ensure that we didn’t miss any of the side effects by chance, in the small groups we chose to test first.

 

Why can’t we get through these phases more quickly?

Vaccines are administered to healthy people. By rushing through clinical trials, we might miss some side effects that show up sometime later in test subjects. There have been such cases in the past, an example being: a combined mumps, measles, rubella and varicella vaccine (MMRV) resulting in a condition called febrile convulsions which is the technical term for seizures in a child caused by a spike in body temperature. [2]

As a precautionary measure against such situations, several bodies for vaccine surveillance have been established across the globe.

Regulatory review and approval: After clearing all levels of clinical trials, the vaccine developer has to submit a Biologics License Application (BLA) to the FDA. Next Step: Await approval! 

Manufacturing: Once the FDA gives the green signal, it’s production time. Vaccines are manufactured in large numbers by major drug manufacturers. 

Quality control: Finally, there are procedures that allow stakeholders to track a vaccine’s performance. These include additional trials, the Vaccine Adverse Event Reporting System (VAERS) and the Vaccine Safety Datalink.

Here’s an example of how this process pans out for the Flu-vaccine:

But there’s a catch here, this is not a one time ritual for influenza. Flu vaccines are manufactured every year, based on the design that scientists across the globe come up with. 

Why do we have this annual ritual of updating vaccines?

Some of these viruses just won’t stop mutating! Think about it!

You create vaccines having some particular viral part (protein, DNA, RNA) in mind and the next time this virus attacks, it has slyly managed to acquire spare parts that don’t trigger off your exquisite-trap!

This happens because the genetic material of viruses, in general, is prone to a lot of changes that confer both advantages and disadvantages to its survival. But slowly, favourable changes are selected and they get to a stage where they develop features we have never seen before. This is when we know it is a real cause for concern.

This is not the case for all viruses. Yay. Most of them have a mutation rate (a measure of the changes in the genetic material) that ensures that the virus doesn’t change considerably, hence our vaccines last long enough. Influenza is an exception and so is HIV the vaccine to which is still out of our grasp. Other challenges that scientists face as they try to create a vaccine include a lack of good animal models to study the disease. 

How then do we go about tackling these situations? 

One way is to predict the mutations and update the vaccine as mentioned before. Another approach is one that was born out of our need to respond rapidly in cases of a pandemic. It is called the Vaccine Rapid Response Platform. 

One pioneer of this approach is the Centre for Epidemics Preparedness and Innovations (CEPI) which was started in 2017. CEPI, which is an innovative global partnership between public, private, philanthropic, and civil society organisations funds research in rapid vaccine development. Production of vaccines using this platform starts even before the labs procure the sample of the viruses. They start as soon as the researchers get the genetic sequence of the infecting organism. 

With the DNA sequence, scientists employ various molecular biology techniques to produce the vaccine. It is along these lines that DNA and RNA vaccines gained popularity recently. In this case, the genetic material that codes for certain parts of the virus is introduced into cells of our body, like the skin cells.  Our own cells then produce the antigen and trigger the immune system. This process cuts down on vaccine development time because the scientists don’t have to culture the whole virus. The potential risks of working with live pathogens are also reduced.

In the case of RNA vaccines especially, our cells are capable of producing multiple proteins from the same mRNA template. This amplification provides a quantitative advantage per molecule compared to providing individual proteins.[3]

Another approach is to administer antiviral drugs that are already present in the market for treatment against the disease. Sometimes the mechanism of action of these drugs might also affect the virus in question, hence if it works, these drugs can help control an outbreak until vaccines are ready to be administered. 

It takes longer to read this article than it took to get that last vaccine shot no?

A lot goes into making a vaccine with contributions from the industry, academia, government agencies, and health professionals. A huge shout-out to these people who are also in the frontline of our battle against this outbreak! Stay home and stay safe everyone!

 

References:

  1. https://publichealthonline.gwu.edu/blog/producing-prevention-the-complex-development-of-vaccines/
  2. https://www.nature.com/articles/473436a
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631684/
  4. https://www.intechopen.com/books/current-issues-in-molecular-virology-viral-genetics-and-biotechnological-applications/vaccines-and-antiviral-agents#B6

 

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