mRNA vaccines: A brief history of time

Covid-19 pandemic has ravaged the world throughout 2020. Amidst public health measures that varied across the globe, from full compliance to calling Covid19 a hoax, the scientific community was quietly working on the development of a vaccine for Covid-19. Here is a summary of vaccines for SARS-Cov-2, both approved and in development.

Vaccines Approved	Vaccines in Development
Pfizer, BioNTech’s BNT162b2	Bharat Biotech’s Covaxin
Moderna’s mRNA-1273	Univ of Oxford-AstraZeneca’s AZD1222
Sinovac’s CoronaVac	...
Russia’s Sputnik-V	...
Russia’s EpiVacCorona
China’s BBIBP-CorV

mRNA vaccines give our immune system genetic instructions to recognize the virus, without at any point in time introducing the virus (dead or alive or part or weakened) itself! An mRNA sequence is synthesized for virus’s spike protein (S-protein) and this sequence is introduced into our cellular mechanism to allow our cells to make the spike protein and thereby induce an immune response. The synthetic mRNA is packaged in a lipid nanoparticle that delivers the instructions to the cells. Once inside the cell, cellular machinery follows mRNA instructions to produce the viral spike protein, which then induces an immune response. This is not science fiction – this is real life! We insert instructions to our cells to make a protein from it that looks like a virus protein. The body then builds an immune response to that protein, so in future, if you are ever exposed to the virus, the immune system recognizes that spike protein on the virus and then destroys it before it can enter the cells!

I decided to put together a history in timeline for two most popular vaccines today, Moderna’s and Pfizer’s, which are both mRNA based vaccines.

What you may have heard or read:

Time	Description
64 days	Time it took Moderna to develop their vaccine and launch phase I trial
Jul 2020	Phase III trials began
Dec 2020	The vaccines were ready for deployment and around 3million people worldwide have already been vaccinated.

While everything you have heard and read is correct, the devil though is in the detail and there is a need to understand and appreciate the background work carried out by many scientists and particularly Katalin Kariko in most adverse conditions. In any scientific endeavour, there are hundreds and thousands of scientific researchers who give their everything and largely go unnamed, but in the success of both Moderna and Pfizer is one individual – Katalin Kariko!

I have tried to take descriptive narration out and summarize the history in a tabular form captured as a timeline. Hopefully this is useful, readable and informative.

Time	Description
1961	Messenger RNA (mRNA for short) was discovered by 9 scientists including Francis Crick (of the Crick-Watson double helix fame), Jacob, Brenner and Meselson (of the famous Meselson-Stahl experiment)
1976	Kariko first came to know mRNA in details after attending seminar in Hungary and became inspired to use it for therapeutics
1985	She moved to US from Hungary and joined Temple University as faculty
1990	Kariko moved to Univ of Pennsylvania (Upenn) following a dispute with her boss at Temple University who threatened to deport her.
1995	Through early nineties, she continued her work on using mRNA for drugs and therapeutics, but was not able to generate funding, as all her grant applications were rejected. Eventually, UPenn gave her 2 options – either leave or prepare for demotion
1995	Same year, she was diagnosed with Cancer – so given her circumstances and her desire to pursue research for using mRNA for therapeutics, she decided to stay on and take the humiliation of a demotion at Upenn
1997	In front of a largely dysfunctional copier machine, she met Drew Weissman, who had recently joined Upenn and had approved grants. He became interested in her work and decided to partly fund her experiments and started a partnership
2005	Kariko and Weissman published a paper announcing a modified form mRNA – which is congenial to easy acceptance by the immune system. Normally, we know of 4 bases in DNA, namely, A, T, C and G. In RNA, the T is replaced by a U. Their paper talked of replacing the U with 1-methyl-3’-pseudouridylyl in a synthetically created mRNA. This is generally denoted by greek letter, ψ. For next 5 years, no additional funding came, not much interest was generated.
2010	Derrick Rossi got inspired by her paper and founded Moderna
2010	Kariko and Weissman licensed their technology to small German company BioNTech.
2012	UPenn refused to renew her faculty contract (since demotion) and told her “she was not faculty quality”
2013	Kariko accepted senior VP role at BioNTech
2017	Moderna began developing Zika virus vaccine based on mRNA
2018	BioNTech and Pfizer started co-working on development of mRNA vaccine for influenza. The landmark paper of 2005 and use of ψ is an integral part of the Pfizer’s vaccine.
Jan 2020	Within weeks, Chinese scientists had sequenced the SARS-Cov-2 virus. A synthetic mRNA sequence is extracted that corresponds to the spike protein. Vaccine’s trick #1: A clever lipid packaging system delivers this (synthetic) mRNA into our cells.
Feb 2020	Pfizer’s vaccine development revolved around the use of ψ in mRNA sequence. Vaccine’s trick #2: Cells are extremely unenthusiastic about foreign RNA and try hard to destroy it before it does anything. But the vaccine needs to go past immune system. The use of placates the immune system and interestingly it is however treated as a normal U by relevant parts of the cell.
Mar 2020	In 64 days, Moderna had completed the development of their mRNA vaccine and BioNTech had also reached similar completion stage.
Jul 2020	Phase III trials began
Nov / Dec 2020	The world is ready for vaccination with two leading mRNA vaccines that are 95% efficacious!

In scientific pursuit, never follow only the news in the media – it serves us better to find the whole truth. The vaccines were not developed in one year, as claimed – they are largely a result of tireless pursuit of one woman over 3 decades along with other inspired scientists who ensured that the recipe was ready, come Jan 2020. Technically speaking, we have waited 59 years since 1961 for this day! Yes, the arrival of SARS-Cov-2 virus definitely fast paced the latter development.

Katalin Kariko is directly responsible for the Pfizer vaccine, while an inspiration to Rossi and why Moderna was created! Remember the name, she might just feature in the news as a future Nobel Laureate!