The COVID-19 pandemic spurred unprecedented advances in many aspects of biomedicine. Among the most astonishing was the rapid development of mRNA vaccines, a technology for which Drs. Karikó and Weissman were awarded the 2023 Nobel Prize in Physiology or Medicine (Nature 2021;597:318-24; Scand J Immuno 2023;98:e13340).
mRNA vaccines were in development well before the arrival of COVID-19. Vaccines comprising mRNA transfected dendritic cells were tested against melanoma, prostate cancer, and ovarian cancer in 2010 and 2011 (NCT01066390; NCT01197625; NCT01334047). mRNA vaccines were tested for use against rabies (NCT02241135), Ebola (NCT02485912), and HIV (NCT02888756). This long history of research and clinical trials at Moderna and BioNTech (among others) led to the seemingly miraculous introduction of an effective vaccine in December 2020, almost exactly a year after the first reports of a mysterious respiratory illness in Wuhan, China, and less than a year after COVID-19 was labeled a pandemic.
A mathematical model published in The Lancet Infectious Disease estimated that COVID-19 vaccines saved more than 14 million lives in the first year after their introduction (Figure 1) (Lancet Infect Dis 2022;22:1293-1302). By March 1, 2023, the U.S. administered over 672 million COVID-19 vaccine doses (asamonitor.pub/46iltda). BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) were the primary vaccines used in the U.S. (Immunopharmacol 2023;117:109934). One of the key advantages of mRNA vaccines is their efficient and simple production process, minimizing the risk of contamination during manufacturing (Signal Transduct Target Ther 2022;7:94). Another advantage is that the target of mRNA vaccines can be readily modified by changing the mRNA sequence to match the currently circulating COVID-19 variants.
“It has been clear for two years that the choice was to get vaccinated or get COVID-19. Given a choice between acquiring immunity from a small dose of spike protein (mRNA vaccine) or a large dose of spike protein (getting COVID-19), we can’t think of any rationale for choosing the large dose.”
The biggest disappointment of the COVID-19 vaccines (all of them) was that immunity from infection was relatively short-lived. This should never have been a surprise. William Haseltine wrote in July 2020 that “we know from nearly 60 years of observing coronaviruses that even if a body’s immune system can clear the virus, the pathogen can likely reenter the system and cause illness again” (asamonitor.pub/3ufi80E). This followed work by Edridge and colleagues demonstrating that throughout our lifetimes, we are reinfected with seasonal coronaviruses every three to four years (Nat Med 2020;26:1691-93).
Despite waning efficacy against infection, vaccine efficacy against severe disease, hospitalization, and death is far more robust (Lancet 2022;399:924-44; Nat Commun 2023;14:4325). Vaccines have effectively curbed the pandemic’s impact across various age groups and vulnerable populations, marking a significant milestone in the fight against COVID-19. However, as the virus continues to evolve, concerns about waning vaccine efficacy and rare adverse events have prompted discussions on improving mRNA vaccine formulations and exploring alternative vaccination strategies (J Biomed Sci 2022;29:82).
Adverse events related to mRNA vaccines
While clinical trials did not identify any serious adverse effects that would prevent vaccine approval, post-authorization administration revealed rare adverse events with varying symptoms, raising important safety concerns.
One concerning issue is the occurrence of myocarditis and pericarditis, particularly among males under 40 years of age, following vaccination (Int J Mol Sci 2023;24:5944). Although the risks are relatively low, they are higher with certain vaccines, such as ChAdOx1, and the first dose of BNT162b2 (Int J Mol Sci 2023;24:5944). Additionally, some individuals over the age of 75 have experienced myocardial infarction, stroke, and pulmonary embolism after vaccination, underscoring the importance of monitoring and assessing risk factors (Int J Mol Sci 2023;24:5944).
Alterations in the menstrual cycle, including abnormal bleeding and delayed menstruation, have been observed following BNT162b2 vaccination (Int J Mol Sci 2023;24:5944). While the exact mechanisms behind these changes are not fully understood, they highlight the need for continued research into potential vaccine-related effects on reproductive health.
It is also worth noting that alcohol, tobacco, and drug use can decrease the humoral vaccine response and may also enhance metabolic responses to the spike protein, including the rare neurological complications Guillain-Barre syndrome and Bell’s palsy (Int J Mol Sci 2023;24:5944).
The mRNA vaccine is transcribed by muscle cells near the site of vaccination into the spike protein. Of course, the amount of spike protein synthesized by the body by infection with SARS-CoV-2 is far greater than the amount of spike protein synthesized in response to the mRNA vaccine. It is therefore not surprising that the risk of myocarditis and pericarditis is five-fold higher after infection with SARS-CoV-2 than after vaccination (Nat Med 2022;28:410-22). COVID-19 infections are also associated with alterations in menstruation (J Psychosom Obstet Gynaecol 2023;44:2238243). Additionally, the incidence of Guillain-Barre syndrome occurs in about 1% of patients with neurological sequelae following COVID-19, far higher than the rare incidence reported with vaccines.
The documented serious adverse events with mRNA can be traced to the spike protein encoded by the injected RNA message. By design, this is the same spike protein that is encoded by SARS-CoV-2 RNA. Fortunately, the mRNA vaccines do not seem to be associated with any complications that are not more common than the complications of COVID-19 itself.
There is the less serious adverse event of feeling really sick, similar to the onset of influenza or some other awful viral illness. Be glad if you feel lousy after vaccination, because the aches and malaise are caused by your immune system ramping up in response to an unwelcome visitor: the spike protein. If you feel fine after vaccination, then your immune system isn’t doing its job.
Nearly the entire U.S. population now has antibodies to SARS-CoV-2 (J Insur Med 2023;50:49-53). It has been clear for two years that the choice was to get vaccinated or get COVID-19. (ASA Monitor 2021:85; 1,7). Given a choice between acquiring immunity from a small dose of spike protein (mRNA vaccine) or a large dose of spike protein (getting COVID-19), we can’t think of any rationale for choosing the large dose.
mRNA vaccine myths
Misconceptions have surrounded COVID-19 vaccines since their introduction. To briefly summarize (and debunk):
- The mRNA vaccines were inadequately tested. This is a matter of opinion. The Pfizer BNT162b2 vaccine was tested in 38,000 patients, half of whom received the active vaccine. The Moderna vaccine was tested in 30,000 patients, again randomized 1:1. The agency tasked with this determination, the U.S. Food and Drug Administration (FDA), believed that the data supported safety and efficacy. The FDA is very scrupulous, and there is no reason to believe they approved anything that did not meet regulatory guidelines. The Pfizer and Moderna briefing documents reviewed by the FDA are publicly available (asamonitor.pub/47uOAdD; asamonitor.pub/47uvi8r). Other false claims (e.g., the companies did not conduct animal trials before human tests, all vaccines are experimental, etc.) are readily addressed by reading the reports.
- Vaccines, and not COVID-19, are responsible for the excess deaths during the pandemic. It is obvious that this is nonsense by looking at excess mortality, as shown in the Figure. The rise in excess deaths was evident from the first days of the pandemic, well before vaccines were introduced.
- The Vaccine Adverse Event Reporting System (VAERS) database demonstrates millions of vaccine complications. This is addressed exceptionally well in an article by The Associated Press (asamonitor.pub/40A39dP). The uncredited writer seems tired of debunking this, based on his or her statement, “Claims about the safety of the vaccines based on data from VAERS have been debunked by The Associated Press on multiple occasions.”
VAERS is a surveillance system intended to broadly capture anybody’s adverse experience following vaccination. It is self-reported, which means that the information gathered has all of the vagaries of patient self-reporting. Most anesthesiologists will immediately recognize this problem. How many of your patients have self-reported allergies to propofol, or “all antibiotics,” or even oxygen?
VAERS requires expert analysis for assessment. The reports in VAERS are carefully adjudicated by the Centers for Disease Control and Prevention (CDC), the FDA, pharmaceutical companies, and medical researchers (asamonitor.pub/3EQCrUm). All have a very strong vested interest in arriving at the correct inference on vaccine safety. The actual rates of serious complications are a very small fraction of the rates suggested by the VAERS reporting system.
- Natural immunity is “better” than immunity acquired by vaccination. This claim is not obviously wrong. It may have arisen as a backlash to vaccination requirements that did not accept infection as a method of acquiring immunity. A recent meta-analysis suggests that vaccination and infection provide equivalent immunity (J Infect Public Health 2023;16:1137-41).
However, vaccination obviously is not associated with the risk of death, hospitalization, serious illness, and long COVID associated with COVID-19. A more subtle difference is that vaccination is also not associated with the risk of autoimmune disease that is seen after infection with SARS-CoV-2 (Nat Commun 2023;14:1299).
- mRNA vaccines can change your DNA. mRNA does not enter the nucleus and does not alter DNA. This post reviews one such claim about a study conducted in Sweden and includes a debunking by the study’s authors (asamonitor.pub/47B7xf3).
- Vaccines don’t cause COVID-19 variants (another popular myth trending on social media); they help prevent new variants by reducing virus spread (asamonitor.pub/3EQCrUm).
- mRNA vaccines include a live virus. This is false. Vaccination with an mRNA vaccine does not lead to viral shedding.
- mRNA vaccines include biological material from aborted fetuses. Nope. They are completely synthesized, with no biological components whatsoever.
- mRNA vaccines have microchips designed to track everyone. If this is a concern, then you need to better understand how your cell phone works (it tracks you constantly).
- mRNA vaccines magnetize people. Really? How exactly do you magnetize a person? I don’t see a lot of people walking around a cafeteria attracting the utensils.
The future of mRNA vaccines
As mRNA vaccines have become a cornerstone in the fight against COVID-19, the question of what the future holds for this innovative technology looms large. mRNA vaccines have proven their effectiveness and versatility, but they are not without challenges.
One promising avenue for mRNA vaccines in the future is the expansion of their application to other infectious diseases. One great example is the promise of the mRNA vaccine in treating melanoma, which we covered in the July In the Know column (ASA Monitor 2023;87:1,4). Furthermore, mRNA vaccines have demonstrated their potential in combating a range of infectious diseases in animal models, encompassing influenza, Zika, Ebola, cytomegalovirus, and even HIV (Int J Mol Sci 2023;24:5944). This versatility suggests the potential for mRNA vaccines to address a broad spectrum of infectious threats.
The adaptability of mRNA technology makes it well-suited for responding to emerging infectious threats. Unlike traditional vaccine development, which often involves lengthy timelines, mRNA vaccines can be rapidly designed and produced once the genetic sequence of a pathogen is known (Signal Transduct Target Ther 2022;7:94; Int J Mol Sci 2023;24:5944). This flexibility is a game-changer in our ability to respond swiftly to new disease outbreaks.
However, challenges remain in ensuring equitable access to mRNA vaccines globally. The initial distribution of COVID-19 vaccines highlighted disparities in access, with high-income countries securing the majority of early vaccine supplies (J Glob Health 2022;12:03072). Efforts must continue to ensure that mRNA vaccine technology benefits all nations, particularly those with limited resources.
The issue of vaccine hesitancy and misinformation is another challenge that mRNA vaccines, like all vaccines, face (J Gen Intern Med 2022;37:179-87). Addressing concerns and providing accurate information about vaccine safety and efficacy are crucial in building public trust and promoting vaccination.
Future vaccine formulations may also need to consider the inclusion of additional viral targets. While the spike protein has been the primary focus of current COVID-19 mRNA vaccines, emerging variants may necessitate broader immunity. Researchers are exploring the potential inclusion of other viral proteins, such as the N and M proteins, in vaccine formulations to enhance immune responses (Int J Mol Sci 2023;24:5944).
Additionally, efforts should be made to reduce T-helper 17 (Th17) responses, which have been linked to adverse effects in some COVID-19 vaccines (Int J Mol Sci 2023;24:5944). Fine-tuning vaccine formulations to minimize these effects while maintaining strong protection against the virus is an ongoing challenge.
Striking the right balance between the benefits and risks of mRNA vaccines remains crucial in our ongoing efforts to combat SARS-CoV-2 and future infectious threats. Continuous research, monitoring, and innovation will be pivotal in harnessing the full potential of mRNA vaccine technology while addressing challenges and ensuring global health security.
As we learned in medical school, vaccines are the cornerstone of public health interventions against infectious diseases. Vaccines nearly eliminated some of the most feared diseases of prior centuries. mRNA vaccines have turbocharged vaccine discovery and development. They presage advances in biomedical technology needed to address future pandemics and ensure global health security.