The Moderna mRNA Vaccine, Phase 1

5 Things We Need to Know – and Why We Should Celebrate (a Bit)

By Shlomo Maital    

A sign of the times: A jargon-filled academic article published in the New England Journal of Medicine,* about a very small Phase 1 trial of a COVID-19 vaccine, has stock markets rising, or even soaring, social media buzzing, …. But — what is this really about? What is the state of Moderna’s vaccine, in simple language, as Moderna gears up for massive Phase 3 trials?

     Here are 5 things you need to know and understand.   From what I understand, the Moderna vaccine IS a big deal. It offers us great hope. Let’s try to understand why. This blog is long – nearly 1,500 words.

   First – what’s the story about Moderna?

     Moderna is a US biotech company based exclusively on messenger RNA (mRNA) (see below), in Cambridge, Massachusetts. (RNA is ribonucleic acid.)

     Messenger RNA is RNA that tells the ‘ribosome’ (the protein factory inside the cell) which proteins to make and how to make them, by assembling amino acids.

   The Moderna technology inserts synthetic (manmade) mRNA into living cells in order to reprogram the cells to develop immune responses. It is a novel technique abandoned by several large pharmaceutical and biotechnology companies who all failed to overcome the side effects of inserting RNA into cells. As of May 2020, no mRNA drug had been approved for human use. Moderna’s decision to try to develop a COVID-19 vaccine based on this risky unproven technology was a huge leap of faith. And, it may have worked.

    Previously, Moderna conducted mostly failed trials with AstraZeneca, and in orphan diseases with Alexion Pharmaceuticals. In 2014, Moderna moved to focus on lower-margin mRNA vaccines. The strategic change led industry experts, and even Moderna employees, to question whether the company would survive. It looked bleak.

     In December 2018, Moderna became the biggest initial biotech public offering of shares (IPO) in history, raising US$600 million for 8% of its shares, implying that the company was worth $7.5 billion – this, despite cumulative losses of $1.5 billion and equity raised of $3.2 billion.

     As of May 2020, Moderna was valued at $30 billion, but none of its mRNA molecules had reached large clinical trials, and several had failed due to side-effects. It looked like a bubble to many.

   And then came the huge leap into the unknown – the race to create a COVID-19 virus.

     In July 2020, Moderna announced that its mRNA COVID-19 vaccine candidate in Phase 1 clinical testing had led to production of neutralizing antibodies in healthy adults. * And – the side effects were not serious (headaches, nausea). The article was peer-reviewed in the leading medical journal, New England Journal of Medicine.

   Now, here are a few more things we need to know, from a trusted website.**


  1. “Vaccines based on messenger RNA are a whole new type of vaccine   If an mRNA vaccine was approved for coronavirus, it would be the first of its type. ‘It’s a very unique way of making a vaccine and, so far, no (such) vaccine has been licenced for infectious disease,’ said Prof. Isabelle Bekeredjian-Ding, Paul Ehrlich Institute, Germany

     “Vaccines work by training the body to recognize and respond to the proteins produced by disease-causing organisms, such as a virus or bacteria. Traditional vaccines are made up of small or inactivated doses of the whole disease-causing organism, or the proteins that it produces, which are introduced into the body to provoke the immune system into mounting a response.

   “But mRNA vaccines, in contrast, trick the body into producing some of the viral proteins itself. They work by using mRNA, or messenger RNA, which is the molecule that essentially puts DNA instructions into action. Inside a cell, mRNA is used as a template to build a protein. ‘An mRNA is basically like a pre-form of a protein and its (sequence encodes) what the protein is basically made of later on,’ said Prof. Bekeredjian-Ding.

     “To produce an mRNA vaccine, scientists produce a synthetic version of the mRNA that a virus uses to build its infectious proteins. This mRNA is delivered into the human body, whose cells read it as instructions to build that viral protein, and therefore create some of the virus’s molecules themselves. These proteins are solitary, so they do not assemble to form a virus. The immune system then detects these viral proteins and starts to produce a defensive response to them.

   This is crucial. Vaccines are traditionally made by weakening or killing the virus or bug that causes illness. If they are not made properly, they can make people ill. So manufacturing them is very difficult, costly and time-consuming.   mRNA vaccines are not dangerous, because the RNA they introduce triggers an immune reaction, but it cannot cause the illness itself!

  1. The mRNA vaccines could be more potent and straightforward to produce than traditional vaccines

“There are two parts to our immune system: innate (the defences we’re born with) and acquired (which we develop as we come into contact with pathogens). Classical vaccine molecules usually only work with the acquired immune system and the innate immune system is activated by another ingredient, called an adjuvant. Interestingly, mRNA in vaccines could also trigger the innate immune system, providing an extra layer of defence without the need to add adjuvants.

   ‘All kinds of innate immune cells are being activated by the mRNA,’ said Prof. Bekeredjian-Ding. ‘This primes the immune system to get prepared for an endangering pathogen and thus the type of immune response that is triggered is very strong.’

   “There is still a lot of work to be done to understand this response, the length of the protection it could give and whether there are any downsides.   Prof. Bekeredjian-Ding also explains that because you’re not introducing the whole virus into the body, the virus can’t mount its own self-defence and so the immune system can concentrate on creating a response to the viral proteins without interference by the virus.   And by getting the human body to produce the viral proteins itself, mRNA vaccines cut out some of the manufacturing process and should be easier and quicker to produce than traditional vaccines. ‘In this situation, the major benefit is that it’s easy to produce (and) it will also probably be relatively easy to do an upscaling of production, which of course, is very important if you think about deployment throughout Europe and the world,’ said Prof. Bekeredjian-Ding.   ‘It’s a very unique way of making a vaccine and, so far, no (such) vaccine has been licenced for infectious disease.’

  1. There are a lot of unknowns. “Because mRNA vaccines are only now beginning to be tested in humans, there are a lot of fairly basic unknowns which can only be answered through human trials. ‘What is really the current challenge, I think, is to understand whether these vaccines will really be able to mount a sufficiently protective immune response in the human and to understand, for example, which quantities of mRNA will be needed to do this,’ said Prof. Bekeredjian-Ding.

   “Other outstanding questions include whether the proteins that have been chosen for the vaccine are the right ones to prevent a coronavirus infection in the body, how targeted the immune response is to this particular coronavirus, how long any immunity would last, and whether it causes side-effects such as increased inflammatory responses like redness and swelling or, in the worst case, aggravates disease.”

  1. It would be possible to vaccinate on a large scale. (NOTE: THIS IS A BIGGIE!)

   “Once an mRNA vaccine has been approved, which could take 12-18 months, it should be easy to scale up production. Because the manufacturing process is shorter than for other vaccines – Prof. Bekeredjian-Ding estimates a few months rather than 1-2 years for conventional vaccines – there is potential for these vaccines to be scaled up quickly. This is useful in the context of coronavirus, which will likely need mass immunization programs.

   ‘I think we will need a very high population coverage, but it depends a little bit on the countries and the epidemiology,’ said Prof. Bekeredjian-Ding. ‘In the countries where coronavirus has been spreading very fast, we also expect that there’s many people who have been in contact with the virus and who have actually mounted a natural immune response. But on the other hand, if you look at Germany, for example, right now we’re all at home, barred, and not allowed to leave the house except for necessities.

   And…I can’t resist adding this. The Chief Medical Officer of Moderna is Dr. Tal Zaks. He is Israeli. He studied at Ben Gurion University of the Negev.  Regarding Moderna’s vaccine, he said that its experimental anti-COVID-19 vaccine “actually works,” after tests on a small number of volunteers, and that it will start Phase 3 testing on thousands of people in July.

   “We got the first results today… and today we are showing that it actually works… we are able to stimulate the immune system,” Dr. Zaks said.

Dr. Zaks believed in Moderna’s mRNA vaccine from the outset, when many did not.  Can we hope that this vaccine will end up saving many many lives, all over the world?

* An mRNA Vaccine against SARS-CoV-2 — Preliminary Report New England Journal of Medicine. July 15, 2020.