The Moderna mRNA vaccine candidate has significant side effects.

Updated to add this link to a Wired article: Covid-19 Vaccines With ‘Minor Side Effects’ Could Still Be Pretty Bad.

On July 14th, the New England Journal of Medicine (NEJM) published a preliminary report on a study of the mRNA vaccine candidate for Covid-19 by Moderna: “An mRNA Vaccine against SARS-CoV-2.” The good news is that the vaccine works. It produces antibodies, and the antibodies are sufficient to destroy the virus. The not-so-good news is that there are side effects, mild to moderate side effects in 100% of test subjects who received both doses.

A vaccine stimulates the immune system to produce antibodies. These antibodies are proteins which recognize a virus as foreign. However, the antibodies cannot recognize the whole virus, but only a subsection of a viral protein, called an epitope. The antibodies attach to the foreign protein, at the epitope, signaling to the immune system cells to attack the virus as a whole.

Your body will naturally perform this process by itself, recognizing an infection via the adaptive (or acquired) arm of the immune system, and in about 14 days after the infection begins, the antibodies will be able to begin clearing your system of the virus. The purpose of a vaccine is to develop these antibodies in advance, so that, if you are infected with the virus, the immune system clears it right away. This can either result in an absence of the disease entirely, or a milder and shorter course of the disease.

Vaccines are never 100% effective. Some percentage of vaccinated persons will or at least can be infected with the virus. But the vaccine should help them in any case, since the immune system will recognize the virus much more promptly. The yearly flu vaccine in the U.S. is 40 to 60% effective, but only when the vaccine matches the strain that causes that yearly flu []. Sometimes the flu that spreads throughout the nation is different from the vaccine, and it is far less effective, as little as 19% effective [2014-2015 flu season,]. It is possible that the Covid-19 virus could mutate into a strain which is so different from the current version, that any vaccine would be less effective, by degrees somewhat less effective. But as of the present time, the current set of strains are similar enough that any vaccine should work.

The Moderna vaccine is a new type of vaccine, never used in a large population before. It is an mRNA vaccine. The Coronavirus, officially called SARS-CoV-2, is a single strand of RNA, wrapped in protein, and surrounded by a lipid bilayer membrane (similar to the lipid bilayer of human cells). The virus drops its RNA into an infected cell, and the cell mistakenly thinks the RNA is its own messenger RNA (mRNA), sent from the nucleus of the cell. And so the cell makes the proteins coded into the viral RNA. The vaccine is a smaller stretch of the viral RNA, which also impersonates mRNA. It codes for one particular viral protein.

How does this mRNA from the vaccine get into our cells? It is surrounded by lipid nanoparticles, which form a type of container for the mRNA. The container can enter the cytoplasm, the interior, of our cells because the cell membrane is a lipid bilayer. So there is no obstacle to the nanoparticles and the mRNA inside to move into the cells.

The protein, coded into the mRNA of the Moderna vaccine, is the Spike protein. These Spike proteins form a set of hundreds of Spike-shaped protrusions surrounding the viral membrane. These Spikes, on an electron micrograph, look like a crown surrounding the virus, hence the name Corona Virus (or “crown virus”). So the vaccine is a piece of RNA which, when it enters the cytoplasm of human cells, makes the Spike protein by itself, without the rest of the virus. The immune system recognizes that Spike protein as foreign, and develops antibodies against it. Then, if you are infected with the Coronavirus, the immune system recognizes those Spikes all around the outside of the virus, and the immune system attacks it right away.

Usually, the virus gets to replicate and spread throughout your body for about 14 days before the adaptive arm of the immune system starts producing antibodies to start clearing the virus. This is partly because the virus is good at hiding from the innate arm of the immune system, which is the first responder against an infection, and partly because the virus blunts the response of the innate arm by attacking it directly (as explained here). With a vaccination, the adaptive arm of the immune system starts attacking the virus almost immediately.

Phase I Trial

Let’s delve into some specifics of the Moderna Phase I trial for its mRNA vaccine. The 45 test subjects, 18 to 55 years of age, were divided into three 15-person groups. Each group received a different dosage of the vaccine: 25, 100, or 250 µg of the vaccine, and they received the dose twice, 28 days apart. So it takes two vaccinations about a month apart for this vaccine to work. When vaccinating a large population, that is a problem. You have to make sure that everyone who is vaccinated returns for a second shot a month later. The reason for the different doses was to determine which dose is most effective, with the least side effects. It turns out that all three doses produced working antibodies, in higher amounts with higher doses. But the side effects were also higher with increasing dosage. So Moderna has decided to use the intermediate dose of 100 micrograms (µg) for Phase II and Phase III trials.

“After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens.” [1]

So by a month after the second vaccination (day 57), all 45 participants had antibodies similar to the “upper half” of persons who had recovered from Covid-19. The upper half means those recovered patients with the highest amounts of antibodies, the top 50%. So the vaccine is very effective. It is as good as having had and recovered from Covid-19, with a healthy immune system.

“On the basis of the results obtained in patients at these dose levels, additional groups were added to the protocol; those results will be reported in a subsequent publication.” [1] So the study was expanded to add more participants, and that data is not presented in this report [1].

Side Effects

The side effects from this vaccine are significantly more than for a flu vaccine or an MMR vaccine. However, in this trial, only 45 persons receiving the first vaccination shot, and three less received the second vaccination (42). Two dropped out of the 25 µg dose group, and one dropped out of the 250 µg group; none dropped out of the 100 µg group.

Note: Side effects discussed below are detailed in the main article [1] and in the supplementary appendix [2].

The side effects were greater after the second vaccination than the first. As stated, the 45 test subjects were divided into three 15-person groups, and they were given 25, 100, and 250 micrograms of the vaccine, in two stages. The 100 µg dose is the one selected for the phase 3 trials and, perhaps, for the commercial vaccine.

In the 25 µg group, one person had raised red itchy blotches (urticarial, i.e. hives) on both legs, and did not receive the second vaccination. This may have been an allergic reaction. But only one in 45 persons reacted with hives on both legs.

The side effects in response to the 250 µg dose are perhaps irrelevant, as the 100 µg dose was chosen as the candidate vaccine. So let’s take a look at the side effects for the first and second dose of the 100 µg vaccine.

“Any Systemic Symptom” — a systemic symptom is one that affects a body-wide organ system, such as the nervous system, the cardiovascular system, the skin, the digestive system, etc. If a symptom is not systemic, then it is local, occurring only in one place in the body (often at the site of vaccination). After the second 100 µg dose, 100% of participants (15) had “any systemic symptom” — 20% mild and 80% moderate.

Mild was defined as not interfering with daily activities; moderate, as some interference with daily activities; severe, as preventing daily activities.

After the first and second 100 µg dose, 13.4% of participants (2 each time) had joint pain, one mild and one moderate. After the first 100 µg dose, 20% (3) had mild fatigue and 6.7% (1) had moderate fatigue. After the second 100 µg dose, 40% (6) had mild and 40% had moderate fatigue, for a total of 80% of vaccinated persons experiencing fatigue after the second dose.

After the second 100 µg dose, 33.3% (5) had a mild fever and 6.7% (1) had a moderate fever. There was no fever after the first vaccination at that dosage level. After the second 100 µg dose, 80% had chills, mostly mild, and 60% had a headache, 33.3% mild and 26.7% moderate.

After the second 100 µg dose, 53.3% of participants had muscle pain, mostly moderate, and 46.7% had nausea, mostly mild. After both the first and the second 100 µg dose, 100% of participants had local symptoms, mostly local pain, long with some swelling and/or redness.

Other symptoms, judged to be related to the vaccine by the researchers, included a total of 35 (out of 45) persons who had symptoms from an organ class related to the vaccination. These side effects included: 2 eye disorders, 5 gastrointestinal disorders, 8 general disorders and/or vaccination site reactions, 1 infection, 5 metabolism or nutritional disorders, 3 muscular or skeletal or connective tissue disorders, 2 lightheadedness or fainting, 1 mild psychiatric disorder, 1 mild reproductive or breast disorder, 2 respiratory or thoracic disorders, 1 vascular disorder, and 4 skin or subcutaneous tissue disorders.

What If?

How will this vaccine be used if it is brought to a commercial release? How many persons will receive this vaccine in what space of time? 100,000 vaccinated persons means 100,000 persons with side effects, as 100% of test subjects (100 µg dose) had one or another side effect by the second shot.

One person had hives on both legs, from the lowest dose (25 µg) and the person chose not to continue to the second vaccination. What percentage and number of persons would react this way if 100,000 are vaccinated? It’s too small a sample size to say how often the side effect of hives may occur. But at one out of 45, it is unlikely to be a rare effect.

More troubling is the side effect of fatigue, which was mild in 40% of vaccine recipients and moderate in another 40%. If you vaccinate a million persons, that’s 800,000 persons with fatigue, and half of them with fatigue severe enough to interfere, to some extent, with daily activities. Now as the vaccine trials continue, these numbers might change. They might get smaller as a percentage, but they also might get larger.

Then there were the side effects, affecting organ systems, which were “unsolicited”. This term means that they asked the patients about certain types of symptoms, whether they had pain at the vaccination site, whether they had a fever or fatigue or muscle pain, etc. But then there were other symptoms that were reported by the test subjects, symptoms not included in the questions from the researchers. There were 35 out of 45 subjects reporting organ system symptoms from the vaccinations [2, table S3]. That’s 77.7% with these types of symptoms. Needless to say, if you vaccinate 100,000 persons in a short period of time, you might have many persons going to the doctor’s or the hospital with symptoms from the vaccination.

Another problem is that, when you have a larger group of persons receiving a vaccine (or a medication), you find reactions that do not show up in a test with 45 participants (only 15 of which received the dosage which is now aimed at commercial release). If a symptom occurs in 1% of recipients, it might not show up in those 15. If a symptom shows up in 10 or 20% of recipients of the vaccine, it might not show up in any of the 15. And the hives reaction is particularly troubling, as an allergic reaction from the 25 µg dose indicates that allergic reactions might be worse if they occur in the first or second shot for the 100 µg dose. At a level of 100,000 or one million vaccine recipients, what kinds of allergic reactions might show up?

Another issue is that some of the persons being vaccinated, in a commercial release with 100k or more recipients of the vaccine, might already have Covid-19 and not know it. You can’t test everyone before vaccinating them. It would be too expensive, and time consuming, and some persons might not return for the second time to receive their first shot, and then for the third time to receive their second shot. So you will be vaccinating some persons who have the virus, and the side effects will combine with the symptoms of the disease, making it worse.

Most persons who die from Covid-19 are over the age of 60 years. If you vaccinate 100,000 of such persons, in order to protect their lives, elderly persons with co-morbidities are most in need of protection, and also most in need of the vaccination. But the vaccination has side effects in 100% of recipients. The side effects in elderly persons, especially those with comorbidities, might outweigh the benefits of the vaccine. But they are the ones who need it most, since most deaths from Covid-19 occur in the elderly.

Next Phases

The NEJM article about Moderna vaccine mRNA-1273 states the following about future vaccine trials:

“A phase 2 trial of mRNA-1273 in 600 healthy adults, evaluating doses of 50 µg and 100 µg, is ongoing ( number, NCT04405076. opens in new tab). A large phase 3 efficacy trial, expected to evaluate a 100-µg dose, is anticipated to begin during the summer of 2020.” [1]

The phase 2 trial is described here at There are four arms, each with a placebo and an intervention subgroup:
1. 50 µg vaccine or saline placebo, ages 18 to 54
2. 50 µg vaccine or saline placebo, ages 55 and up
3. 100 µg vaccine or saline placebo, ages 18 to 54
4. 100 µg vaccine or saline placebo, ages 55 and up

Moderna seems to realize that they need to evaluate this vaccine in its effects particularly on the elderly. Not only do they have the above trial, with two age groups, but another trial with three age groups.

Moderna has a different phase 1 trial of the mRNA-1273 vaccine based on the age of the recipients: 18-55, 56-70, 71 and up here. Results are expected soon according to this news article.

The phase 3 trial may have as many as 30,000 participants. “Moderna plans to begin a clinical trial with 30,000 participants at the end of this month to determine how effective the vaccine is.” [WBUR Common Health] The phase 3 trial tests the vaccine against the virus. This is done by vaccinating a large number of persons who are at risk of Covid-19. Then, as the trial proceeds, they look for more persons to be infected in the placebo group than in the intervention (vaccinated) group. The assumption is that the level of risk is about the same in each group, so if the vaccinated group has fewer cases, the vaccine is protective.

Some commentators have suggested speeding up the vaccine testing by deliberately infecting vaccinated persons with Covid-19 to see how well the vaccine works sooner. But that is not a procedure being used or planned for use by any vaccine company. The Moderna phase 3 trial will use a wait-and-see approach. They are deliberately testing the Vaccine in the U.S., because of the recent opening of the nation and increase in cases. They declined to test the vaccine in Israel, where the company began, because that nation has a strict lockdown which is keeping cases low.

Here’s an interesting exchange from an interview of a chief scientist at Moderna, Dr. Tal Zaks, with a news organization in Israel:

“Where do you vaccinate people? Are you looking for specific areas?

“We are conducting this research in the United States. We are examining the spread of the virus and plan on opening research centers in the most heavily affected areas so that we can effectively test our vaccine on the local population – public servants, medical staff, etc. If I am to conduct this research here in Israel on people who remain in their homes, the chances of finding those who actually get infected is lower.” [Jerusalem Post]

The company deliberately targets the U.S. and particular areas within the U.S. that have a high case rate, so that the vaccinated persons will be “challenged” by the virus sooner and in greater numbers.

Can the company deliver enough doses of the vaccine, if needed? Moderna noted in a press release:

“the Company remains on track to be able to deliver approximately 500 million doses per year, and possibly up to 1 billion doses per year, beginning in 2021”

I doubt that this vaccine will be suitable for such a widespread use, given its extensive side effects. And the competition for a successful Covid-19 is intense. There are over 120 other vaccine candidates in the works, including a few close on the heels of Moderna for an early 2021 release. An mRNA vaccine has never been fielded before, and it seems that the side effects might be more than for other types of vaccines.

Ronald L. Conte Jr.
Note: the author of this article is not a doctor, nurse, or healthcare provider.

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1. Jackson, L., et al. “An mRNA Vaccine against SARS-CoV-2 — Preliminary Report.” NEJM, July 14, 2020
DOI: 10.1056/NEJMoa2022483

2. Supplementary Appendix; Supplement to: Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2 — preliminary report. N Engl J Med. DOI: 10.1056/NEJMoa2022483

Click to access nejmoa2022483_appendix.pdf