How safe is a vaccine developed in record time?

A lot of people I know are concerned about the safety of the coronavirus (SARS-CoV-2 vaccine), and they should be! We are in the midst of a global pandemic and there is a massive incentive to address it so we can return to normal life. The vaccines have been approved in record time and the leading vaccine candidates rely on mRNA technology, which has never been used in a vaccine before. This may all sound scary, so is it safe to take the vaccine?

First and foremost, let’s define what a safe vaccine means and how to apply it. Vaccine safety is not the same for all diseases. For example, a technique called variolation was used a few hundred years ago in China to prevent smallpox infection, where healthy people inhaled smallpox scabs through their nose resulting in a mild case of smallpox, ¹1 (a shot in the arm doesn’t sound so bad now, does it?) although 0.5-2% of people still died. This sounds like a pretty bad deal until we consider the infection fatality rate of smallpox was 20-30%.

COVID-19 is not smallpox 2.0 (fortunately), and the infection fatality rate is relatively low compared to the deadliest viruses, so the vaccines for it need to be safer than they would be for a disease like smallpox or HIV. It is quite difficult to determine the overall infection fatality rate for COVID-19, as it varies quite a lot in different regions. It ranges from 0.09% in Kenya to 2.28% in New York City.2 This is undoubtedly largely affected by how old a population is in each country and if this older population (65+) gets infected. In my age group of 30-34, the infection fatality rate is around 0.037%,2 but my parents’ age group of 70-74 is 2.3%, ²2 which is fairly concerning. Basically, the vaccine had better be pretty damn safe if I’m going to take it. Those over 80 have an infection fatality rate of 8.29%, and with people in nursing homes it is a staggering 22%,2 so your safety threshold may be different if you are older.

Now, onto the vaccines. You may have never heard of mRNA until now, but it is a crucial part of protein synthesis, which is the main substance our bodies are made of after water. RNA is a type of nucleic acid, like DNA, but it is less stable and it isn’t used as an information database like DNA. If RNA gets mutated it’s very unlikely to result in cancer as can happen with DNA. DNA gets transcribed into mRNA, which gets translated into proteins. Traditional vaccines typically work by injecting an inactive virus or segments of an inactivated virus into the body to generate an immune response. This can be challenging because sometimes the inactivated virus will not induce a potent immune response so adjuvants such as aluminum sulfate are needed to increase the immune response. With mRNA vaccines, the mRNA within the vaccine uses your cell’s natural machinery to make a specific viral protein or proteins that the body will develop an immune response against. Since the mRNA only codes for one part of the virus, there is no possibility of being infected from the vaccine. For the Pfizer/Moderna coronavirus vaccines, the mRNA codes for the spike protein on the surface of the coronavirus, which triggers your body to produce antibodies that will neutralize the coronavirus if you are exposed to it. Antibodies will then be produced after vaccination, and if coronavirus enters your body, antibodies in your blood will bind to the coronavirus and remove it from the body.

Drug discovery investigating mRNA as a therapeutic has been around since 1990 and I actually had a very low-level position in an RNA company 9 years ago. It’s taken a long time to get RNA research off the ground because RNA gets degraded very quickly in the body and it is very challenging to get it inside of cells to have an effect. RNA requires a type of shield to prevent it from getting degraded and this is typically done with a lipid nanoparticle which is basically a tiny bubble (100 nanometers in diameter, or 50 times smaller than a cell) with RNA inside. There have actually been 2 RNA drugs that have recently been FDA-approved in 2018 and 2020 (Patisiran and Givlaari), although these are composed of small interfering RNA, a type of viral RNA that blocks protein synthesis. Small interfering RNA is a different type of RNA, but the delivery is quite similar, and Patisiran actually uses two of the same lipids in its lipid nanoparticle that the Pfizer and Moderna vaccine use (cholesterol and DSPC). ³3 This may alleviate some of the concerns about the rapid development of this vaccine.

Nanoparticles sound scary, is this a concern? Yes, nanoparticles can certainly have safety issues, they are incredibly challenging to make with precision, and if there are vast differences in particle size there can be differences in toxicity. ⁴4 Storage and stability can also be problematic, which is why the vaccine must be kept at very cold temperatures. I haven’t seen data on the stability of this vaccine, so I can’t comment on how this may influence safety, but lipid nanoparticle drugs are actually not new, and the first one (Doxil) was approved in 1995. This drug is a lipid nanoparticle containing the anticancer drug doxorubicin which actually reduced toxicity compared to doxorubicin alone. ⁵5 This may offer some comfort for the safety of the coronavirus vaccine. In the next instalment of this series I will go through all of the ingredients in the vaccine and their potential impact on safety. Here they are:

Active Ingredient: Nucleoside-modified messenger RNA (modRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2

Lipids: (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis (ALC-3015), (2- hexyldecanoate),2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide (ALC-0159), 1,2-distearoyl-snglycero-3-phosphocholine (DPSC), cholesterol

Salts: Potassium chloride, monobasic potassium phosphate, sodium chloride, basic sodium phosphate dihydrate

Stabilizer: Sucrose

So, how did a whole new type of vaccine get developed so fast? Well, unsurprisingly, mRNA vaccines were not developed overnight. As of 2017, there were 26 clinical trials ongoing or completed for mRNA vaccines. The results of these studies were that the vaccines were generally well-tolerated by humans, but there were some issues. ⁶6 One thing that does not happen, is incorporation of mRNA into your cell’s DNA, which could lead to cancer and other diseases. Since mRNA is structurally different to DNA, there is no way that vaccine mRNA can combine with DNA inside your cells. The only way RNA can be incorporated into DNA is if there is an enzyme called reverse transcriptase present, which reverse transcribes RNA into DNA, but this is a viral enzyme only present if you have uncontrolled HIV (and it wouldn’t be a contraindication with this vaccine anyway).

The coronavirus mRNA vaccines were developed at ‘warp speed’ because to make an mRNA vaccine, all you need is the genetic sequence of the virus you are trying to immunize against. Since the genetic sequence of coronavirus was very quickly identified, labs were able to produce mRNA sequences that coded for the spike protein of coronavirus. This is also an advantage if any mutations of the virus come out. The new more infectious UK coronavirus variant B.1.1.7 is expected to be covered by the approved vaccines, ⁷7 but if not, mRNA vaccines can be rapidly modified to protect against new strains. The next reason why vaccines can take a long time to develop is that it is unethical to directly infect patients with a deadly virus. This means to test effectiveness you need to deliver your vaccine or placebo in the general population and wait for them to naturally get exposed to the virus. Since the epidemic went uncontrolled in so many areas of the world, it didn’t take long for enough people to naturally get infected to evaluate the effectiveness of the vaccine.

Now for general safety. I mentioned earlier that mRNA vaccines do not require adjuvants, this means there is no aluminium sulfate in the vaccine, and they are also preservative free, so there is no mercury either. That does not mean they are 100% safe, and there were some significant adverse events reported. Here are some of the results from the FDA study for the Pfizer vaccine. Both the placebo group and vaccine group had over 18,000 participants, which a pretty big sample size to assess safety.
Here is a breakdown of the results. ⁸8

• There were more adverse events in the vaccine group (27% compared to 12% for placebo).
• Redness, swelling, and pain at the injection site was comparable between the vaccine and placebo.
• Fatigue and headache were the most common symptoms (50% in the vaccine group compared to 23% in the placebo group)
• Fever of 38.9 to 40°C (102-1040 F) was reported in 0.2% of vaccine recipients and 0.1% of placebo recipients. Fever greater than 40°C was reported in two people in both vaccine recipients and placebo recipients
• 0.3% of vaccine recipients and .03% of placebo recipients experienced lymphadenopathy, or swollen and enlarged lymph nodes.
• There were 4 incidents of Bell’s palsy in the vaccine group (0.021%) which could be worth monitoring, but is most likely unrelated to the vaccine (Bells Palsy affects 0.01-0.04% of the population annually) ⁹9
• There were 4 serious adverse events (0.021%) in the vaccine group, which were a shoulder injury related to vaccine administration (I’d like more details on how this one happened…), right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia. There were two deaths in the vaccine group, but 4 deaths in the placebo group.
• Safety over 2 months was determined to be similar to that of other approved vaccines. ⁹9

Long term safety is unknown, but long-term issues are exceedingly rare with vaccines. If you are a person who has severe immune reactions, it may be advisable to wait for more data to come out before taking the vaccine. Two people in the UK with a history of severe immune reactions experienced this.¹⁰10 Before I did research for this, I was actually pretty sceptical of mRNA vaccines. How can we trust a brand-new type of vaccine developed in less than a year with enormous amounts of economic and political pressure to get it released? After my research, the science looks pretty good, but that doesn’t mean significant issues won’t arise.

Would I take the vaccine? I would if I was a front-line health worker, or over 65, the benefits of the vaccine outweigh the risks. If I was a 30-year-old in America, and it was available, I would probably wait a couple months for more safety data to come out. Since I live in New Zealand without any community spread, I’m at a very low risk of coming in contact with the virus, so as of now the vaccine doesn’t seem necessary for me, but this will change once our borders open up. We can think about whether you should take the vaccine using a risk-management perspective.

Currently (17/12/2020) the CDC puts the excess deaths between 291,000 and 400,000 for 2020. ¹¹11 For the sake of this evaluation, let’s split the difference and say 345,000 people have died of COVID-19 in the US in 2020, and if we assume a mortality rate of 0.6% which was published for the US as of October 23rd, 2020²2 (I’ll also not-so-humbly say I estimated an IFR of 0.61% back in April) that gives us a total of 57.5 million coronavirus infections for 17.5% of the population of the US. With over 200,000 people getting infected every day, I think it is safe to say at least 60% of the US population will eventually get infected with coronavirus at some point if we did not have a vaccine. So, let’s say there is a 50% chance you will get infected with coronavirus, and in my age group of 30-34, if I got infected there is a 0.037% chance that I would die, not to mention the other serious effects COVID-19 can have even if you survive. Cut that in half and there’s a 0.019% chance that I’ll die, (if you have pre-existing conditions this would be higher and if you did not it would be lower). Now if I take the vaccine, which has an efficacy of 95%, there is a 0.021% chance that I’ll have a severe adverse event. Personally, I’d take the very small risk of an adverse event over the very small risk of death, but you can make up your own mind.

Jonathan Falconer has a Ph.D. In Pharmaceutical Chemistry from University of Utah and works as a Teaching Fellow in Pharmacology at the University of Otago in New Zealand. He also co-hosts a podcast on material science produced by The MacDiarmid Institute called 15 Minutes Smarter. Follow him at instagram.com/doctorfalco. and twitter.com/thatfalconer

References:

1. Tang, Jin-Ling, Bao-Yan Liu, and Kan-Wen Ma. “Traditional chinese medicine.” The Lancet 372.9654 (2008): 1938-1940.
2. O’Driscoll, Megan, et al. “Age-specific mortality and immunity patterns of SARS-CoV-2.” Nature (2020): 1
3. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210922s000lbl.pdf
4. Jones, Clinton F., and David W. Grainger. “In vitro assessments of nanomaterial toxicity.” Advanced drug delivery reviews 61.6 (2009): 438-456.
5. Safra, T., et al. “Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2.” Annals of Oncology 11.8 (2000): 1029-1033.
6. Pardi, Norbert, et al. “mRNA vaccines—a new era in vaccinology.” Nature reviews Drug discovery 17.4 (2018): 261.
7. https://apnews.com/article/europe-europe-coronavirus-pandemic-united-states-8555f433c0cd8ea8c58040e3f7aa0e91
8. Polack, Fernando P., et al. “Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine.” New England Journal of Medicine (2020).
9. Ahmed, Anwar. “When is facial paralysis Bell palsy? Current diagnosis and treatment.” Cleve Clin J Med 72.5 (2005): 398-401.
10. https://www.npr.org/sections/coronavirus-live-updates/2020/12/09/944539982/u-k-regulators-tell-people-with-severe-allergies-not-to-get-vaccine
11. https://www.cdc.gov/nchs/nvss/vsrr/covid19/excess_deaths.htm