Health

Nobel Prize In Medicine 2023: Research That Led To The Development Of mRNA Covid-19 Vaccines

October 2, 2023
Bharat Times

Nobel Prize in Physiology or Medicine 2023: Hungarian American biochemist Katalin Karikó and American physician Drew Weissman have been awarded the 2023 Nobel Prize in Physiology or Medicine. They received the Nobel for their contributions to the field of immunology that led to the development of effective mRNA vaccines against Covid-19. Karikó and Weissman’s discoveries on nucleoside base modifications provided key insights into developing mRNA Covid-19 vaccines that not only don’t induce inflammatory reactions in the host organism, but also enable enhanced protein production. Base-modified mRNA can block the activation of inflammatory reactions.

The Pfizer-BioNTech Covid-19 vaccine, the Moderna Covid-19 vaccine, and Gemcovac-19, India’s first indigenously developed mRNA Covid-19 vaccine, are the only authorised mRNA vaccines available in the world. 

Karikó and Weissman’s research is groundbreaking because their findings led to the development of two base-modified mRNA vaccines that could encode the surface or spike protein on SARS-CoV-2, allowing the production of this protein in the body of the host organism injected with the vaccine. This elicited an immune response in the host organism, enabling their body to identify SARS-CoV-2’s spike protein, which is the antigen, in case the virus truly entered the person’s body. The two Covid-19 vaccines are the ones developed by Pfizer-BioNTech and Moderna in late 2020. These were highly successful, saved millions of lives, and prevented severe disease in a large number of people. 

mRNA vaccines: How they work, and what their advantages are

The role of vaccines is to introduce small quantities of a pathogen, parts of the microorganism, or a genetic component coding for small amounts of the microorganism’s segments into the body of the host organism to elicit an immune response. Once the body identifies the pathogen, it creates antibodies against the microorganism. As a result, in the case of future infections, the antibodies fight against the antigen, preventing disease in the host organism. It is important to ensure that a harmless piece of the bacteria or virus is introduced into the body of the host organism. 

While most vaccines contain a weakened or inactivated pathogen, mRNA vaccines use a molecule called messenger RNA (mRNA), which serves as a template for protein production. 

In the human body, the genetic information present in DNA is transferred to mRNA. This process is known as transcription. The production of proteins from mRNA is known as translation. 

According to the US National Institutes of Health (NIH), mRNA vaccines do not alter the DNA because the mRNA does not enter the nucleus of a cell. These vaccines introduce a piece of mRNA that can code for a protein present on the virus. In the case of SARS-CoV-2, the viral protein is the spike protein. Therefore, mRNA Covid-19 vaccines against SARS-CoV-2 use mRNA that codes for the spike protein of the novel coronavirus. 

Once the mRNA enters the cells of the host organism, it directs the cells to produce copies of the spike protein, and as part of a normal immune response, the immune system recognises the protein as an antigen, and produces antibodies against it. If the virus enters the body of the host organism in the future, the antibodies recognise the antigens, attach themselves to the spike proteins, and mark them for destruction. In this way, severe disease is prevented. 

mRNA vaccines are promising because their production is not a resource-intensive process, as a result of which they can be produced at a rapid rate. Also, if base modifications are introduced in the mRNA, inflammatory response is prevented, and protein production is increased in the cells in which mRNA is introduced.

It is these discoveries that won Karikó and Weissman the Medicine Nobel. 

Therefore, mRNA vaccines are advantageous because they can be developed with flexibility and at record speed. 

Traditional vaccines

Before the Covid-19 pandemic, there were no mRNA vaccines. Whole virus-based vaccines such as those against polio, measles and yellow fever were available. These contain attenuated or killed viruses.

Subsequently, protein- and vector-based vaccines were developed. Scientists make proteins with the help of viral genetic code, and then use the proteins to make the vaccines. Once the vaccine is injected into an individual, virus-blocking antibodies are produced. The vaccines against hepatitis B virus and human papillomavirus are protein-based vaccines. 

Protein subunit vaccines use a part of the pathogen’s protein. Corbevax is a receptor-binding domain protein subunit vaccine against Covid-19, and uses a part of the spike protein of SARS-CoV-2. 

Vector-based vaccines are the ones in which a harmless carrier virus is used to carry parts of the viral genetic code. 

 

Traditional vaccines are mainly of three types: whole virus-based, protein-based, and vector-based. Whole virus-based vaccines introduce attenuated or inactivated pathogens to the host, protein-based vaccines introduce components of the pathogen’s protein into the host, and vector-based vaccines introduce a viral vector which instructs the host’s cells to code for proteins that will serve as antigens in the body of the host organism, eliciting an immune response. (Photo: The Nobel Committee for Physiology or Medicine)

The vaccine against Ebola virus is a vector-based vaccine. 

Covishield, Sputnik V, Janssen, and Oxford-AstraZeneca’s Covid-19 vaccine are examples of viral vector vaccines against SARS-CoV-2. 

Covaxin is an inactivated vaccine, and Covovax is a nanoparticle-based vaccine in which the receptor-binding domain of the spike protein of SARS-CoV-2 is attached to a protein designed to form nanoparticles which improve vaccine efficacy. 

The challenges associated with mRNA vaccines, and how Karikó and Weissman overcame these

Although mRNA was successfully produced without cell culture, as part of a process of in vitro transcription, it was initially unstable and challenging to deliver because sophisticated carrier lipid systems had to be developed to encapsulate the mRNA. Also, in vitro-transcribed mRNA triggered inflammatory immune reactions. This is one of the main reasons why interest in using mRNA technologies for vaccine and therapeutic purposes was initially limited. 

This is where Karikó comes into the picture. In the late 1990s, Karikó and Weissman met while they were photocopying research papers, according to the University of Pennsylvania. After this, they started working together to find solutions to use mRNA as a therapeutic. Weissman, an immunologist, was interested in dendritic cells, which play an important role in the immune response induced by vaccines. 

Karikó and Weissman observed that dendritic cells recognise in vitro transcribed mRNA as an antigen, as a result of which the cells were activated. This released inflammatory signalling molecules in the body. However, when dendritic cells were exposed to mRNA from mammalian cells, the former did not recognise the mRNA as foreign. It was this anomaly that Karikó and Weissman decided to decipher.

RNA contains four nitrogenous bases: Adenine, Guanine, Thymine, and Cytosine. In mammalian cells, such bases are frequently chemically modified. But this modification does not occur inside in vitro transcribed mRNA. 

Therefore, Karikó and Weissman started wondering if in vitro transcribed mRNA induces an unwanted inflammatory reaction due to the absence of altered bases.

In order to see if this is true, the scientists produced different variants of mRNA, each of which had unique chemically altered bases, and delivered them to dendritic cells. 

How base-modified mRNA paved the way for effective mRNA Covid-19 vaccines

Karikó and Weissman were surprised to see that mRNA with base modifications did not trigger an inflammatory reaction. This finding is crucial because it provides the world an understanding of how cells recognise and respond to different forms of mRNA. 

The finding made Karikó and Weissman realise that it had immense significance for using mRNA as a therapeutic agent, and published their results in the journal Immunity in 2005. They concluded in the study that nucleoside modifications suppress the potential of RNA to activate dendritic cells. 

 

Karikó and Weissman were surprised to see that mRNA with base modifications did not trigger an inflammatory reaction. This finding is crucial because it provides the world an understanding of how cells recognise and respond to different forms of mRNA. (Photo: The Nobel Committee for Physiology or Medicine)
Karikó and Weissman were surprised to see that mRNA with base modifications did not trigger an inflammatory reaction. This finding is crucial because it provides the world an understanding of how cells recognise and respond to different forms of mRNA. (Photo: The Nobel Committee for Physiology or Medicine)

Karikó and Weissman wrote in studies published in 2008 and 2010 that base-modified mRNA, when delivered to cells, will increase the production of proteins, compared to unmodified mRNA. 

Karikó and Weissman’s discoveries that base modifications in mRNA not only reduce inflammatory responses, but also increase protein production paved the way towards the development of mRNA vaccines. 

In 2010, the interest in mRNA technology peaked, and firms started working on developing vaccines using this method. The Zika virus vaccine, which is still investigational, is an mrna-based vaccine. The MERS-CoV vaccine, which is under development, is also an RBD-based mRNA vaccine. 

Pfizer-BioNTech and Moderna used this technology to develop highly effective Covid-19 vaccines. Since December 2020, more than 665 million doses of mRNA vaccine doses against SARS-CoV-2 have been administered. These vaccines offer protective effects of around 95 per cent. 

Since mRNA vaccines can be developed at record speed, mRNA technology can be explored to produce vaccines against other infectious diseases, and to deliver therapeutic proteins to different parts of the body. 

Karikó and Weissman, through their groundbreaking contributions to mRNA technology, have helped the world evade a gargantuan health threat.