If there was any silver lining to the wide swath of destruction caused by the coronavirus, it was that the COVID-19 allowed humanity to pool its resources and create marvelous new technologies. Perhaps no greater success story from the pandemic exists than the development of several COVID vaccines in under a year’s time. 

They represent, by far, a record pace for the development of a vaccine against any microbe. It is particularly impressive that the vaccines were made against a virus that uses RNA as its genetic code, as those viruses have historically been difficult to figure out. The fact that these three vaccines happen to be some of the most effective one in human history is nothing short of astounding. 

Vaccines represent some of the most powerful and enduring advancements in medicine. Their development began during the Industrial Revolution, when, as the story goes, Edward Jenner noted in 1796 that milkmaids who had been exposed to cowpox did not get infected with the highly contagious disease smallpox. 

It led to the development of the first successful vaccine, which gained wide acceptance in the coming years and steadily declining numbers of a previously deadly disease. Two centuries later, smallpox had been completely eradicated.  Though its origin story is probably an apocryphal one, it represents one of the biggest success stories in the history of public health. 

In order to better appreciate the differences between the three commercially available COVID-19 vaccines in the United States, it’s important to answer a few basic questions: What is a vaccine? How do vaccines work? How do you know if a vaccine works? How do you know if a vaccine is safe? Which vaccine side effects are most likely? This article aims to answer these questions

The Basics of Vaccines

Let’s start with some fundamentals: a vaccine is a preparation that assists the immune system (the body’s natural defense system against invaders and repair system for damaged cells) in creating immunity against bacteria, viruses and other microorganisms. 

Generally speaking, vaccines work by presenting the body with a form or a part of the microbe that can be recognized by the body without causing harm. Usually this process involves exposing the body to either a weakened version of the microbe or to a component on the surface of the microbe. 

Vaccines typically take years to develop, and often decades before they find widespread acceptance. One of the most well-known examples of this phenomenon is the polio vaccine, first developed by physician Jonas Salk in the 1950s. The polio vaccine has long been considered the gold standard for the development and deployment of a vaccine.

The vaccines developed to reduce transmission and disease severity in COVID-19 broke new ground. More than 100,000 scientific articles have written about COVID-19, a full order of magnitude more than have been penned about HIV and AIDS. Researchers have been able to leverage this knowledge to create effective vaccines in record time— in less than a year. 

The modern development of vaccines usually begins with animal studies to test the vaccine’s general effectiveness. That is followed by studies on human safety, and then again followed by clinical trials for assessment of efficacy. The process usually takes several years. But of course, with COVID-19, time was of the essence; two more years of COVID-19 without a vaccine would have likely resulted in over two million deaths in the United States alone. 

Not only did the vaccines have to be fast, but they had to be effective, either at reducing the severity of the average infection with COVID-19 or at reducing the transmission of the virus. With any luck, the vaccines would be good at both. But at the beginning of 2020, when these vaccines began their development processes, precious little was known about the coronavirus

Not only were the vaccines rapidly developed, but studies showed that they were more effective than nearly any other vaccine in human history. The COVID-19 virus itself was actually helpful in this regard. The main protein that the COVID virus uses to dock to and enter cells in the respiratory system—those familiar red prongs on popular images of the coronavirus— is called the spike protein (or S protein), and it provided a convenient target for each of the vaccines. 

In just five short months after the World Health Organization (WHO), the Food and Drug Administration (FDA) and other leading organizations approved the first COVID-19 vaccine for emergency use, over one billion vaccine doses have been received. Skepticism about these vaccines was high at first, but it has decreased over time as data about their effectiveness poured in (and as the COVID-19 pandemic roared on). 

Three of these vaccines have current approval for emergency use in the United States. They are all highly protective against severe disease and death from COVID-19, and very effective at reducing rates of COVID-19 transmission. Here is a comparison of the differences between vaccines: approved populations, mechanism of action, efficacy, side effect profile and efficacy versus COVID-19 mutations. 

At a glance: 

Pfizer/BioNTechModernaJohnson & Johnson
FDA ApprovalDecember 11, 2020December 18, 2020February 27, 2021
Ages (May 2021)12 and up16 and up18 and up
MechanismmRNA vaccinemRNA vaccineVector vaccine
Effectiveness— 100% against severity/death— 95% against transmission— 90% in “real world conditions”— 94.1% against severe disease— 86% against severe disease in seniors— 90% in “real world conditions”72% overall 
86% against severe disease
DeliveryOne injection, then another in 21 daysOne injection, then another in 28 daysOne injection
Efficacy vs. variants95% against B.1.1.7 (UK) and B.1.351 (SA) variants. “Effective” against B.1.617 (India)“Effective” vs B.1.1.7 and B.1.351.“Appears effective” against B.1.617“Significant protection” against B.1.1.7 and 64% overal effectiveness vs B.1.351.

Pfizer/BioNtech

The first COVID-19 vaccine to receive emergency use authorization stemmed from a collaboration with the American multinational pharmaceutical giant Pfizer and the German immunotherapy company BioNtech. The companies received emergency use authorization from the United States Food and Drug Administration (FDA) on Dec. 11, 2020.

Storage requirements for this vaccine were thought to potentially be a major barrier to its distribution and usage. When the vaccine was approved, temperature requirements were restrictive, as the vaccines required cold storage of -70 to 110 degrees Fahrenheit, necessitating the use of specialized freezers. 

However, data in February 2021 showed that normal pharmaceutical freezer temperatures (around 0 degrees Fahrenheit) resulted in no loss of effectiveness. After removal from the freezer, the vaccine dose can be maintained at normal refrigeration temperatures for five days.

The Pfizer/BioNTech version of the vaccine is the only one, so far, that is approved for early teenagers in the United States; anyone aged 12 and older is approved for emergency use (U.S.).  Evaluation of the vaccine for the 12-15 age group is underway in the European Union, where the vaccine is distributed under the brand name Comirnaty (pronounced “ko-MIR-na-tee”, like “community”).

That name—the middle of it, at least— is meant to evoke the mechanism of this vaccine.  Like its Moderna sibling, the Pfizer/BioNTech COVID-19 vaccine is an mRNA vaccine, a new concept in the world of vaccine development. 

It contains a genetic message for immune cells in the human body to make copies of just the spike protein on the coronavirus surface. Without the rest of the virus to help it infect, the spike protein is harmless to those cells. However, the body uses the spike protein to train the immune system on what it’s looking for, the same way that a hunter might train a bloodhound to recognize the smell of a game animal. 

When the immune system encounters the spike protein, it practices its reaction, creating antibodies that can be used to neutralize the actual COVID-19 virus if it were ever encountered. That “practice” can also lead to the development of some normal side effects that a vaccine recipient might experience.

Those side effects can include fatigue, muscle pain, nausea, chills, and fever, as well as pain, redness and swelling in the arm the vaccine dose was given. Though medical attention is not usually required for side effects, patients should see a health provider if they have concerns about persistent or severe symptoms. 

The Pfizer COVID vaccine requires two doses to confer immunity. After the first dose is administered, recipients wait three weeks (21 days) until they receive the next one. 

The efficacy of the Pfizer vaccine against COVID-19 is impressive. Published studies and Pfizer’s own data show that the vaccine protected against severe disease from COVID-19 100% of the time in clinical trials. 

Further, it protected against infection in COVID-naive patients 95% of the time. When the idealized and controlled conditions of a clinical trial are removed, the vaccine was 90% effective in a CDC “real-world” trial, along with its Moderna counterpart. 

So far, the Pfizer/BioNTech vaccine has been the one most studied against COVID variants. It has shown to be 95% effective against both B.1.1.7 (UK variant) and B.1.351 (South Africa variant); it also appears to be effective against B.1.167, the dominant COVID strain in India.

The two vaccines that completed their development first essentially helped each other across the finish line as they competed to create their products using a new technology. As a result, their vaccines are largely similar. 

Moderna

The American pharmaceutical company Moderna created the second COVID-19 vaccine to receive emergency use authorization from FDA on Dec. 18, 2020. The company used research that had been conducted by the National Institutes of Health to develop the product.

Unlike its Pfizer sibling, the storage requirements were fairly minimal. This vaccine requires only normal pharmaceutical freezer temperatures (around 0 degrees Fahrenheit), and once removed, the doses can maintain normal refrigeration temperatures for 30 days.

As of this writing, the Moderna vaccine is approved for populations aged 18 and older in both the United States and in the European Union. 

Like the Pfizer/BioNTech version, the Moderna vaccine uses mRNA to deliver the genetic message to immune cells to make coronavirus spike proteins basically as target practice. The dosing schedule reflects this, as recipients receive one dose, followed by a second dose 28 days later. Its side effect profile is nearly identical to the Pfizer version.

The Moderna vaccine has high efficacy against COVID-19. In clinical trials, the Moderna version protected against symptoms of COVID-19 94.1% of the time in COVID-naive patients, and 86% of the time in adults 65 and older. As with the Pfizer brand, the Moderna vaccine was 90% effective in a “real-world” trial, without the controlled conditions of a clinical trial (the Centers for Disease Control conducted this trial using both vaccines assigned at random).  Effectiveness against COVID variants with Moderna is less established than with the Pfizer version, with unclear effectiveness against both B.1.1.7 (UK variant) and B.1.351 (South Africa variant). However, results appear promising.

Johnson & Johnson 

The third COVID-19 vaccine to receive emergency use authorization from FDA was Johnson & Johnson’s entry on Feb. 27, 2021. This vaccine also utilized a rather novel technology, though different from its counterparts. The J&J vaccine is known as a “vector vaccine”: it uses a virus that the body has seen many times before, called an adenovirus, to deliver the instructions to cells to make the coronavirus spike proteins. If the Moderna and Pfizer versions of the vaccine are war couriers, the Johnson & Johnson version is more like a Trojan horse.

During the first week of April, the CDC and the FDA issued a joint recommendation to temporarily pause distribution of the J & J vaccine due to six reported cases of rare blood clots in younger women. After investigation, the FDA and CDC lifted the temporary pause April 23, 2021.

Like the Moderna vaccine, the Johnson and Johnson entry is approved for populations aged 18 and older in both the U.S. and the E.U. Its storage requirements are only normal refrigeration, which will keep the vaccine usable for 30 days. No freezer storage is needed. 

Besides its vector vaccine mechanism, the other defining feature of the Johnson & Johnson vaccine is that, unlike the other two entries, it requires only a single dose. Its efficacy, while a little lower than the others, is still very high: clinical trials showed 72% overall effectiveness, with 86% effectiveness against severe disease. 

Potential side effects of the Johnson & Johnson vaccine are the same as with the Pfizer and Moderna varieties, and generally result from the intentional immunity stimulated by the action of the vaccine.  This vaccine shows effectiveness against COVID variants, offering “significant” protection against B.1.1.7 (UK variant) and 64% overall effectiveness (82% effectiveness against severe disease) for the B.1.351 (South Africa variant). Research against the Indian variants is pending. 

What These Differences Mean for Patients

Patients who feel they are making informed choices are more likely to approach the decision about getting vaccinated with confidence and with thoughtful openness.  However, it is of critical importance that patients get up-to-date, accurate and reliable information about the expected benefits and risks in their decision to vaccinate and in their choice of vaccine. 


Jennifer Billings is the Medical Editor at National Coronavirus Hotline(NCH). She is an Integrated medical doctor who has been published on NCH Blog, Medium.com and is a regular contributor at MedCity News, Physician Family, and Psychology Today.