SCI-TECH & AGRI

‘The vaccine was rapidly synthesised as novel coronavirus sequence was available’

Gagandeep KangSpecial arrangementSpecial arrangement

Gagandeep KangSpecial arrangementSpecial arrangement  

Just over three months after the genome sequence of the novel coronavirus (SARS-CoV-2) was shared by Chinese researchers, an messenger-RNA (mRNA) vaccine is being tested at Seattle in a Phase-1 clinical trial on 45 healthy volunteers between the ages of 18 to 55 years over a period of approximately six weeks.

The trial began on March 16 at the Kaiser Permanente Washington Health Research Institute (KPWHRI) in Seattle. The study is evaluating different doses of the experimental vaccine for safety and its ability to induce an immune response in participants.

The vaccine (mRNA-1273) was developed by National Institute of Allergy and Infectious Diseases (NIAID), U.S., scientists and their collaborators at the biotechnology company Moderna, Inc., based in Cambridge, Massachusetts. The Coalition for Epidemic Preparedness Innovations (CEPI) supported the manufacturing of the vaccine candidate for the Phase 1 clinical trial.

Virologist Gagandeep Kang, who is the executive director of the Translational Health Science and Technology Institute (THSTI), Faridabad, in an email to The Hindu explains how the mRNA vaccine is developed and how it has become possible to get the vaccine ready for testing so quickly.

What makes the use of messenger-RNA (mRNA) for the vaccine different from the conventional vaccines and how does it work?

Most of the vaccines we know are based on a whole organism (bacteria or virus, living or dead) or a part of an organism. Usually these organisms cause disease, but to make vaccines, the organism are manipulated by heat, chemical or other biological approaches to ensure that their pathogenicity has been removed. These vaccines, when given to a person, act like an infection, but without producing disease. The parts of the organism which are recognised by the immune response are called antigens, and when they are recognised, an immune response is made, as either antibodies or activated immune cells that protect from disease when the same infection is seen again.

Unlike a usual vaccine, RNA vaccines work by the introduction of an mRNA sequence into the host’s cells. This mRNA codes for a disease-specific antigen. Once inside a cell, the mRNA instructs the cell to produce the antigen, which is recognised by the immune system which makes an antibody or cellular response.

Currently, two forms of mRNA vaccines are been widely developed against multiple pathogens: conventional mRNA vaccines and self-amplifying mRNA vaccines, which are derived from positive strand RNA viruses.

How has it become possible to develop an mRNA vaccine in just about three months? Is it necessary to have the virus to develop the vaccine?

In part, reseachers were able to quickly develop mRNA-1273 because of prior studies of related coronaviruses that cause SARS and MERS.

We have incredible genome sequencing capacity now, and got the SARS-CoV-2 sequence in early January 2020. Since all you need for the mRNA vaccine is the sequence of the pathogen, a vaccine could be rapidly synthesised in the laboratory.

The mRNA can be made synthetically by in vitro transcription or reading of a plasmid DNA template, with a recombinant RNA polymerase. A cap and tail are attached to from a mature mRNA sequence.

No, the virus is not required, but the genome sequence [of the virus] is needed. The messenger RNAs are produced synthetically and this is what makes the technology rapid and reproducible.

Since a particular protein (spike protein) found on the virus is what binds to receptors found on human cells and then infect them, will the vaccine use mRNAs produced for this protein?

The first vaccine to enter human trials is Moderna’s mRNA-1273. This is a novel lipid nanoparticle-encapsulated mRNA vaccine that codes for the full-length prefusion stabilised spike (S) protein.

How do vaccine developers know which mRNAs of the spike protein are produced? How do they select the correct ones to be included in the vaccine?

The gene sequences of the proteins of coronaviruses are known. Even with a novel virus, it is possible to figure out which sequence codes for which protein. Only one mRNA is included and it is selected based on sequence matching.

Are the mRNAs used in the vaccine packed in some protective material or used bare?

In the case of Moderna, the mRNA is stabilised so that is protected from enzymes that might break it down.

Has this vaccine already been tested in animals for safety or is it tested on human volunteers bypassing animal trials? How ethical is this?

The US FDA has approved studies to proceed in parallel so human studies are also being done with the same product. The mRNA platform technology by which the vaccine was made has already been used safely in 1,700 volunteers for other mRNA vaccines. So the FDA will have considered that in its decision. There are always worries about ethics when testing in emergencies, because safety should be paramount for vaccines, but there is, so far, no safety signal [adverse effects] from the Moderna mRNA platform.

With regard to the parallel studies in animals also, one unusual aspect of the mRNA-1273 vaccine is that although other formulations of similar vaccines have been tested on animals, this particular vaccine construct has not been evaluated in the appropriate animal model which is a transgenic mouse expressing the ACE2 receptor. Tal Zaks, Chief Medical Officer of Moderna was quoted in STAT, a news outlet, as saying: “I don’t think proving this in an animal model is on the critical path to getting this to a clinical trial,” He also pointed out that National Institute of Health scientists are “working on nonclinical research in parallel.”

Has there been any instance before when an mRNA vaccine has been tested on humans?

Many candidate vaccines have been produced using this technology and are in various phases of testing. Currently, there are over 20 candidates for infectious diseases and cancers from multiple groups. This is a new technology and, as yet, there are no licensed products.

Will mRNA vaccine produce better protection against the virus than vaccines developed through the conventional route?

We do not know yet what will work and how well, which is why multiple approaches are being taken for vaccine development.

How long will it take before we have a vaccine for commercial use?

It will take at least a year, if not longer.

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