Both vaccines contain modified mRNA that provides the instructions for the synthesis of the SARS-CoV-2 spike glycoprotein antigen. Its mRNA is enveloped in lipid nanoparticles (LNPs) to prevent degradation and enhance uptake into cells.
The vaccine particles are taken up into cells by endocytosis. The vaccine’s mRNA is then used by the cell’s ribosomes in the cytosol to produce SARS-CoV-2 spike glycoproteins. These proteins then migrate to the cell surface and fragments are presented to the patrolling immune cells by proteins structures called major histocompatibility complexes (MHC).
About the vaccines
Pfizer and BioNTech vaccine
The Pfizer and BioNTech vaccine, called BNT162b2, is given by intramuscular injection in 2 doses, 3 weeks apart.
Results to date suggest the vaccine is highly effective.
In a large, randomized, double-blind, placebo-controlled Phase II/III clinical trial that enrolled >43,000 participants, the vaccine has been found to have an efficacy of 95%, at an interim analysis with a median of 2 months follow up, MMWR reports. (1)
According to the FDA briefing document prepared for the FDA’s Advisory Committee on Immunization Practices (ACIP) meeting, “Consistent high efficacy (≥92%) was observed across age, sex, race, and ethnicity categories and among persons with underlying medical conditions as well as among participants with evidence of previous SARS-CoV-2 infection.” (2)
Results to date suggest the BNT162b2 is safe.
According to the FDA, the frequency of serious adverse events was low (0.5%), without meaningful imbalances between study arms with the exception of more frequent, generally mild to moderate reactogenicity in participants <55 years of age, such as fever, headache and pain at injection site. (2)
“The safety profile of BNT162b2 was generally similar across age groups, genders, ethnic and racial groups participants with or without medical comorbidities, and participants with or without evidence of prior SARS-CoV-2 infection at enrollment.” (2)
ModernaTX vaccine mRNA-1273
On December 18th, the FDA granted emergency use authorization of a second mRNA vaccine, called mRNA-1273, developed by ModernaTX, Inc. The vaccine is administered in 2 doses by intramuscular injection 4 weeks apart.
Results to date suggest mRNA-1273 is effective.
Evidence supporting the authorization is derived primarily from a randomized, double-blind, placebo-controlled Phase III clinical trial that enrolled approximately 30,000 participants. Interim findings, using data from participants with a median of 2 months of follow-up, indicate that the Moderna COVID-19 vaccine efficacy after 2 doses was 94.1%. (3) “High efficacy (≥86%) was observed across age, sex, race, and ethnicity categories and among persons with underlying medical conditions. (3)
Results to date indicate mRNA-1273 is safe.
According to the FDA: “Local site reactions and systemic solicited events after vaccination were frequent and mostly mild to moderate. The most common solicited adverse reactions were injection site pain (91.6%), fatigue (68.5%), headache (63.0%), muscle pain (59.6%), joint pain (44.8%), and chills (43.4%); 0.2% to 9.7% were reported as severe, with severe solicited adverse reactions being more frequent after dose 2 than after dose 1 and generally less frequent in adults ≥65 years of age as compared to younger participants.”  There were no anaphylactic or severe hypersensitivity reactions with close temporal relation to the vaccine. (3)
As of December 3, 2020, there were a total of 13 deaths reported in the study (6 vaccine, 7 placebo). These deaths represent events and rates that occur in the general population of individuals in these age groups. The frequency of non-fatal serious adverse events was low and without meaningful imbalances between study arms (1% in the mRNA-1273 group and 1% in the placebo group).” (3)
Q&A with Dr. Deborah Fuller
Dr. Fuller is a vaccinologist and professor of microbiology at the University of Washington.
Q: Can mRNA vaccines like BNT162b2 alter your DNA?
A: Previous research has found that mRNA vaccines do not alter cellular DNA. These vaccines do not include instructions for a viral reverse transcriptase, which would allow the generation of complementary viral DNA that, in theory, could insert into a cell’s genome. Moreover, the vaccine mRNA remains in the cytosol and does not enter the nucleus where genomic DNA is located.
Q: Any chance of a reverse transcriptase making a complementary DNA to incorporate into the genome?
A: No – DNA makes RNA. RNA does not make DNA. It’s a one-way street.
Q: Are these vaccines self-amplifying?
A: Some experimental mRNA vaccines include instructions for a viral replicase that increases production of the viral protein. Such vaccines are called “self-amplifying.” The mRNA used for both the Pfizer and ModernaTX vaccines codes only the viral spike protein and are not self-amplifying.
However, there are 2nd generation mRNA vaccines in development, including one in my lab, that are self-amplifying. To self-amplify, these mRNA vaccines also express another viral protein (replicase) that instructs the mRNA to make multiple copies of itself. Multiple copies of mRNA in the cell can produce more vaccine protein and more vaccine protein can produce stronger immune responses.
Self-amplifying mRNA vaccines are just entering clinical trials now and if they are shown to be efficacious and safe, they could induce stronger immune responses with lower doses resulting in a more cost-effective vaccine.
Q: What is the reactivity to the lipid nanoparticle? The latest issue of Science cites that this vehicle may be quite reactive, at least in other species where it has been used. And if it is, does this negate using it as a vehicle for other future vaccines in a person?
A: The lipid nanoparticle serves 3 functions: 1) It stabilizes the mRNA, 2) it helps deliver the mRNA into the cell and 3) it has adjuvant activity that helps amplify the immune responses.
This adjuvant activity works by stimulating an innate immune response, which helps to increase antibody responses against the vaccine antigen (Spike protein) produced by the mRNA vaccine. That innate response is what causes reactogenicity. But it’s not presented to our immune system in a way that we make adaptive immune responses or antibody. As such, repeated use of the lipid-nanoparticle should not result in the induction of adaptive immune responses that will limit repeated use of lipid-nanoparticles with other vaccines or medicines.
This is in contrast to the vaccines being developed by Johnson & Johnson and Astrazeneca. These vaccines use viral vectors (adenoviruses) to deliver the genetic code that instructs the cell to produce the Spike protein. With these vaccines, we make antibody against both the adenovirus and the Spike protein. The build-up of antibody against the adenovirus with repeated boosting of the vaccine, can, in time, negate potency of these vaccines since the antibody against the virus would block the adenovirus from delivering the mRNA into the cell.
Q: I understand that double-stranded RNAs may form with mRNA vaccines—is this a problem by activating the innate immune system that responds to such structures? And what effect does this have on the efficacy of the vaccine?
A: Double-stranded (ds) mRNA is a potent pathogen-associated molecular pattern or PAMP that is sensed by multiple cellular pathways and can lead to robust, potentially harmful type I interferon production and increased reactogenicity. Advances in mRNA technology in the last decade have resulted in the development of efficient methods to remove ds mRNA through fast protein liquid chromatography (FPLC) and high performance liquid chromatography (HPLC). In addition, nucleoside modifications incorporated into the mRNA sequences inhibit the ability of the RNA vaccines to form ds mRNA.
Q: What is known about which cell types pick up the mRNA? Does this matter to the immune response?
A: The mRNA vaccines are injected into the muscle, and we know muscle cells express the vaccine antigen which is then picked up and presented by antigen presenting cells that present the antigen to the B and T cells that help make antibody. Some mRNA can also get into the antigen presenting cells.
Q: There have been reports of Bell’s palsy among the vaccine recipients. Is that a risk?
A: There were four cases of Bell’s palsy in the Pfizer vaccine group compared with no cases in the placebo group.(2) But the four cases in the vaccine group do not represent a frequency above that expected in the general population. In the ModernaTX, there were three cases in the vaccinated group, one in the placebo group. (5) However, because these cases occurred shortly after vaccination, a link to the vaccine cannot be ruled out. FDA monitoring will continue.
Q: What other vaccines are in the pipeline? How might they compare to the Moderna product?
A: See above regarding 2nd generation self-amplifying RNA vaccines and also adenoviruses under development by Johnson & Johnson and Astrazeneca. While adenovirus vaccines have the potential to build pre-existing immunity against the adenovirus and limit their repeated use, they do have a significant advantage in that they are very inexpensive to produce large numbers of doses, they are more stable and, in the case of the Johnson & Johnson vaccine, it may be able to induce protective immunity in a single dose.
The New York Times has been tracking all the vaccines in development with descriptions of the vaccines and where they are in development and testing.
Q: If we are going to receive a new type of vaccine where little is known about it, are there investigators at UW Medicine who are interested in studying those vaccinated?
A: Yes – there is a large team of investigators who have been studying convalescent COVID-19 patients and are now preparing to study vaccinated subjects. Major questions to address include: What level of antibody protects? What underlying factors influence the response to these vaccines? How durable is the immunity? And many others.