Vaccines have been an essential tool in our ability to turn a raging pandemic into a manageable disease. More than 90 percent of Canadian adults have received at least two vaccine doses, mainly with novel mRNA vaccines which have the greatest efficacy and fewest complications. Our return to a more normal life is due to their success.
It is interesting to go back to articles published in late 2020 when vaccines were undergoing very early trials with the hope of being our best chance of containing the pandemic. Damien Garde published an article in the Boston Globe on November 10, 2020, titled “The story of mRNA: How a once-dismissed idea became a leading technology in the Covid vaccine race”.
At the time there were more than a dozen candidates using different technology, competing to develop a safe and highly protective vaccine. While we now know the superiority and dominance of mRNA vaccine technology, this was not always the case. While mRNA vaccines were made in record time, there were over three decades of research that led to this rapid success. It is much like the “discovery” of a movie star who diligently toiled for decades to achieve sudden stardom.
The path to success
Katalin Kariko is a Hungarian-born scientist who was a key pioneer in developing mRNA technology.1“More than 15 years ago at Penn Medicine, Karikó and Weissman found a way to modify mRNA and later developed a delivery technique to package the mRNA in lipid nanoparticles. This made it possible for mRNA to reach the proper part of the body and trigger an immune response to fight disease.” https://www.pennmedicine.org/providers/profile/katalin-kariko In the 1990s her research was repeatedly and dishearteningly rejected by funding agencies and scientific bodies. Her goal was to create a custom piece of foreign and synthetic messenger RNA (mRNA) to force the body’s own production of protective proteins against infection and disease.
Two major challenges had to be overcome. The piece of mRNA was fragile and when nakedly injected without a coating was rapidly degraded before it could enter cells. As well, the mRNA was considered foreign, thus triggering an excessive immune response to the mRNA itself with undesirable complications. Two key discoveries eventually followed. The modified piece of mRNA altered and thus was cloaked much like a Trojan horse and could thus get into cells without creating an initial overreaction. Additionally, a lipid shell was created to surround the mRNA that prevented its destruction when introduced into the body and also allowed it to enter cells more easily.
This ultimately led a group of scientists to embrace the technology with high hopes for its use. In 2010 they created Moderna, a company whose name stands for “modified RNA” in the hope of producing an array of vaccines and cancer therapies. No product reached the market for 10 years.
Two scientists at a German company BioNTech, founded in 2008, similarly worked on perfecting mRNA vaccine technology, again with no approved drug. In 2020 when urgent collaboration was needed they partnered with Pfizer, a very large and well-funded multinational Pharma company in order to create a coronavirus vaccine. The two companies, Pfizer, a large giant, and Moderna, a much smaller upstart thus competed to produce the first successful mRNA vaccine. Trials of both vaccines started on July 27, 2020, only six months after the SARS-CoV-2 virus was sequenced,2“In January 2020, when an RNA virus was identified as the etiologic agent of the disease soon to be named COVID-19, scientists immediately sequenced its genome. The virus had 79.0% sequence identity to SARS-CoV, and even higher sequence identity of 86.7%-89% with SARS-like coronaviruses originating in bats, with only 50% sequence identity with MERS-CoV.” https://asm.org/Articles/2020/October/SARS-CoV-2-Sequencing-Data-The-Devil-Is-in-the-Gen#:~:text=In%20January%202020%2C%20when%20an,scientists%20immediately%20sequenced%20its%20genome. and thus mRNA pieces of the spike protein could quickly be artificially created to test as a potential vaccine.
The outcome was a remarkable race ending in a tie. Both companies created highly effective vaccines that had very low risk and were initially about 95 percent protective against disease development. The rapidity of development and regulatory approval also led to some ongoing concerns about the long-term risks of this novel technology. Vaccine hesitancy which was always there in the background grew as a result of this anxiety.
After rapidly performed clinical trials and expedited review, on December 11, 2020, the Pfizer vaccine received U.S. FDA emergency use authorization. Approval for the Moderna vaccine came only one week later.
How does the vaccine work?
Pieces of the coronavirus spike protein are manufactured synthetically, coated with a lipid shell, and placed in vials requiring cold storage. The mRNA vaccine is injected into an arm and absorbed by the muscle. The mRNA, protected from degradation by their lipid nanoparticle coating, then gains entry into cells and uses the cell’s protein production capacity. This produces targeted antibodies that latch on to the spike protein of the virus, thus neutralizing it if exposed in the future. The mRNA is not capable of reprogramming your DNA because it does not interact with the cell’s nucleus and cannot change DNA code. Memory B and T cells are also primed, thus capable of a different and enduring added protective benefit.
Where are we now
The vaccines aren’t perfect in regards to sustained protection. Their efficacy wanes too quickly over six months, requiring boosters. Novel strains such as Omicron with many spike protein mutations make the vaccine-induced antibodies less effective since they don’t attach as completely to the mutated viral spike protein. Importantly they remain highly effective against hospitalization and death. Pfizer has already asked for fourth shot approval for those over 65 based on waning immunity. To the frustration of many, we likely will need annual booster protection from COVID-19 much as we do with seasonal flu, but hopefully with more complete protection than occurs with flu vaccines.
The future of mRNA therapies
The major ongoing advantage of mRNA vaccines is the ease of design, lower cost, and speed of production relative to other vaccines. It only takes about three months to create a new vaccine targeted to a specific new variant if needed.
What is truly exciting is the amount of time and money being invested into broader applications of mRNA-induced protection. While a lot of money has been made by these companies, there is great benefit to mankind, with much more to come from the broader application of this technology. There are many exciting opportunities that are being considered.
In March 2022 Moderna announced the development of mRNA vaccines against 15 diseases including HIV, malaria, Ebola, TB, and Zika.3“Of the 15 high-priority disease targets, vaccine development for Ebola, HIV, Zika and Nipah is already underway. Covid-19 is another one on the list, and Moderna is currently working on an omicron-specific booster dose for its current vaccine, as well as a combination Covid/influenza vaccine. Rounding out the disease list are: Chikungunya virus, Crimean-Congo haemorrhagic fever, Dengue, Malaria, Marburg virus disease, Lassa fever, MERS, Rift Valley fever, Thrombocytopenia syndrome and Tuberculosis. Bancel says the company will also be developing combination vaccines, where a dose could immunize against multiple diseases, for regions where that makes sense.” https://www.forbes.com/sites/alexknapp/2022/03/07/moderna-aims-to-make-vaccines-against-15-deadly-diseases-and-the-next-pandemic/?sh=367ca64145da Time will tell how effective these approaches are, however they show great promise in treating stubborn and dangerous diseases.
Albert Bourla a Greek immigrant, a child of Holocaust survivors, and a veterinarian is the current CEO of Pfizer. His recent book Moonshot describes Pfizer’s “Nine-month race to make the impossible possible”. He recently announced the development of new vaccines that can hopefully protect against all variants as well as seasonal flu in one annual longer lasting more effective vaccine shot.
There is also great promise in treating cancer. Conventional immunotherapy uses targeted inhibitors of signalling proteins that help cancer cells grow. While hugely important and effective these drugs also have major side effects. Vaccine technology may be able to target immunotherapy more effectively and specifically against certain cancers. Work is currently underway in the treatment of melanoma and other common cancers.4“Moderna’s cancer vaccine candidate (mRNA-4359) expresses Indoleamine 2,3-dioxygenase (IDO) and programmed death-ligand 1 (PD-L1) antigens. Moderna designed mRNA-4359 with the goal of stimulating effector T-cells that target and kill suppressive immune and tumor cells that express target antigens, and the company is planning to explore initial indications for advanced or metastatic cutaneous melanoma and non-small cell lung carcinoma (NSCLC). Melanoma is the fifth most common cancer in the U.S. It accounts for 5.3 percent of all new cancer diagnoses and 1.5 percent of all cancer-related deaths.” https://interestingengineering.com/moderna-cancer-mrna-vaccine
Hopefully as a result of the challenges of this pandemic and the concentrated effort to limit death and disability by mRNA vaccination much good is yet to come. Future vaccination will likely be voluntary but welcome by most people, especially those with higher risk. New technological advances come with both huge opportunities and some risks. The possibilities of curing difficult to treat diseases or developing effective less toxic cancer therapies are emerging on our horizon. Let’s hope that quality science, responsible manufacturers, and cost-effective solutions lead the way.
