I’ll be updating this page each time I publish new content related to the vaccine so that you can find all mRNA vaccine related information in one place.
Last updated: January 11, 2021
Table of Contents
Covid-19 mRNA Vaccine Efficacy
Originally published in Newsletter Vol.2 №1 – January 10, 2021
I’ve been asked several times recently what it means that the vaccine is “95% effective.”
It does not mean that 95 times out of 100 exposures an individual is protected from contracting Covid. It does not mean that symptoms are reduced by 95% in vaccinated patients who contract Covid – though there likely is a symptom-mitigating effect in vaccinees who contract Covid.
It does mean that the vaccine is effective in preventing symptomatic infection in members of a group of recipients compared to individuals in a placebo group of non-recipients. But, to get a more concrete idea of exactly how effective this vaccine is, it’s worth looking at the actual numbers from the clinical trial and the trial definition of “vaccine efficacy.”
From the most recent publication in NEJM regarding the Pfizer BioNTech Covid-mRNA Vaccine:
“Among 36,523 participants who had no evidence of existing or prior SARS-CoV-2 infection, 8 cases of Covid-19 with onset at least 7 days after the second dose were observed among vaccine recipients and 162 among placebo recipients. This case split corresponds to 95.0% vaccine efficacy (95% confidence interval [CI], 90.3 to 97.6; Table 2).”
How was vaccine efficacy calculated?
“Vaccine efficacy was estimated by 100×(1−IRR), where IRR is the calculated ratio of confirmed cases of Covid-19 illness per 1000 person-years of follow-up in the active vaccine group to the corresponding illness rate in the placebo group.”
Let’s look at the actual numbers.
In the vaccine group, only 9 out of 21,669 participants tested positive for Covid-19 during a roughly 100 day surveillance period after the 2nd vaccine dose.
So, in this time period, the rate of infection in vaccine recipients was 9 out of 21,669 – 0.04%. In other words, 99.96% of vaccine recipients did not have symptomatic Covid-19 during the surveillance period. Compare this to 172 out of 21,686 in the placebo group – 0.8%. This is still a low infection rate, but it is nearly 20 times the infection rate in the vaccine group.
It is important to realize that many people were neither exposed nor tested during the surveillance period. Exposure was dependent on participant behavior, and testing was dependent on reporting of symptoms. There is no reason to believe these factors were unbalanced between the vaccine and placebo groups, but nonetheless, some caution must be used in interpretation of efficacy for these reasons.
However, whichever way you slice this, the bottom line is that the vaccine does in fact appear to be remarkably effective at preventing Covid-19 infections.
Allergic Reactions to the Covid-19 mRNA Vaccine
Originally published in Newsletter Edition No.3 – December 27, 2020
Several days ago, I read with interest this report from sciencemag.org that discusses the possibility that the half-dozen or so severe allergic reactions to the Covid-19 mRNA vaccine may be due to a component of the vaccine called polyethylene glycol. To understand what’s happening with this, it’s important to understand the composition and function of the vaccine.
According to this information sheet from the FDA, “The Moderna COVID-19 Vaccine contains the following ingredients: messenger ribonucleic acid (mRNA), lipids (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]), tromethamine, tromethamine hydrochloride, acetic acid, sodium acetate, and sucrose.” The Pfizer vaccine has similar components.
Messenger ribonucleic acid, or mRNA for short, is a template molecule that allows a cell to construct a particular protein. Under normal circumstances, mRNA is formed in the nucleus of a cell by a process called DNA transcription. Once the mRNA is created, it leaves the nucleus and enters the cytoplasm of a cell to serve as a template for protein synthesis before being degraded and recycled.
One challenge with the development of the Covid-19 mRNA vaccine, as I understand it, was to figure out how to reliably deliver intact mRNA into a cell from the outside-in. To accomplish this, scientists enclosed the mRNA within a lipid vehicle (a sphere of fat – like a droplet of oil). This “synthetic” fat droplet is able to fuse with a human cell membrane and deliver mRNA into the cytoplasm of the cell where it serves as the template for the synthesis of the SARS-CoV-2 spike protein.
The scientists and engineers who designed the lipid vehicle added a chemical group to the lipid particles called polyethylene glycol (PEG for short), in a process appropriately called “pegylation.” This is a technique that has been used for several purposes in various pharmacologic applications. In the case of the Covid-19 mRNA vaccine, pegylation may have been used to stabilize the lipid vehicle. It’s possible that some severe reactions to the vaccine are due to PEG.
To my knowledge, though some of these reactions have been severe and have even required hospitalization, all have been temporary and treatable with typical medications: epinephrine, antihistamines, and steroids.
So, what to do?
It might be reasonable if you’ve had a severe allergic reaction to PEG, or to another component of the vaccine (listed above), to await confirmation of the source of these reactions, or to avoid the vaccine altogether. This decision of course has to be balanced with your risk of contracting and becoming severely ill with, or dying from, Covid-19 itself. This calculation must be done on an individual basis. For those with known anaphylaxis, or severe allergic reactions, but without known reactions to specific components of the vaccine, it’s likely just as safe to receive the vaccine as it is to be exposed to many other unfamiliar medications, foods, or chemicals.
I’ve yet to see expert commentary on preventive measures such as pre-medication with antihistamines (e.g. diphenhydramine) or steroids (e.g. prednisone). But, I think that pre-medication could theoretically be a viable strategy for at-risk vaccine recipients as long as those medications don’t blunt the immunogenic response to the vaccine.
If you do have a history of allergic reactions, you should have at least one, but probably two or more epinephrine auto-injectors in your possession, and one on your person (or at least nearby) at all times. You should also know how and when to use one.
Even those without a history of allergic reactions can save a life with an epinephrine auto-injector. It’s a good idea to ask your doctor for a prescription for one of these regardless of your allergy history.
At this point, the vaccines still appear extremely safe and effective. Keep in mind that despite headlines, only 5-10 severe reactions have been reported in over one-half million doses given thus far. Stay tuned for another update in two weeks.
Covid-19 mRNA Vaccine Update – Pfizer vaccine data
Originally Published in Newsletter Edition No.2 – December 13, 2020
Two weeks ago, I published an article reviewing the data on the mRNA vaccine for Covid-19. Most of the data I reviewed at that time was with regard to the Moderna vaccine.
In the interim, additional information has been released in NEJM about the Pfizer-BioNTech mRNA vaccine demonstrating a similar safety and efficacy profile. You can read that NEJM article here.
Another article in NEJM was released on December 3, 2020 demonstrating persistent antibody mediated immunity for Sars-CoV-2 induced by the Moderna vaccine up to 119 days after the first vaccination. Here is an excerpt:
At day 119, the binding and neutralizing GMTs exceeded the median GMTs in a panel of 41 controls who were convalescing from Covid-19, with a median of 34 days since diagnosis (range, 23 to 54).2 No serious adverse events were noted in the trial, no prespecified trial-halting rules were met, and no new adverse events that were considered by the investigators to be related to the vaccine occurred after day 57.
What does all of this mean? It means that both companies seem to have produced extremely effective vaccines. The safety profiles appear to be excellent. The first non-trial recipients have been vaccinated in the past week. If there are any unforeseen major issues, they should come to light within the next 4-8 weeks. Let us hope that none do.
Covid-19 mRNA Vaccine Information
Information on how mRNA vaccines work, how they’re developed, and Moderna vaccine efficacy and safety data
Originally published in this article – November, 29, 2020
The Moderna and Pfizer mRNA vaccines, which are likely to be available within the next 1-3 months, have been successfully tested in non-human primates and humans. In the non-human primates, the vaccine appears to stimulate the formation of antibodies that inhibit viral replication and prevent symptomatic Covid-19 disease in animals exposed to the virus. Human clinical trials also appear successful with a ten fold smaller incidence of symptomatic Covid-19 infections in vaccine recipients as compared to a placebo group. At this time, no severe adverse events have been reported in vaccine recipients.
There is good reason to believe that the vaccine will confer immunity for at least several months, and possibly years, for almost all recipients including those over age 70.
There is no evidence that I am aware of at this time that the vaccine poses any long term danger to its recipients.
Most of what follows is based on data from the Moderna vaccine and its trials. I think it’s most likely that this vaccine will be more widely available than the Pfizer vaccine given that it can be stored at temperatures achievable by many freezers, whereas the Pfizer vaccine is currently said to require temperatures far colder.
I’ll also say at the outset, I am not an expert in infectious disease or in vaccines. I have done my best to understand and organize publicly available information. My references are listed at the bottom of the page. Please contact me if you have any questions or corrections.
How does it work?
The Moderna and Pfizer vaccines are mRNA vaccines. This vaccine technology is not a brand new idea, but it’s my understanding that this will be the first time it is used in humans for an infectious disease.
The vaccine is a solution composed of messenger RNA (mRNA) inside of lipid nanoparticles and then diluted in sterile saline solution (i.e. salt water). The vaccine is injected into the muscle, and the lipid nanoparticles are taken up by muscle cells. Once in the cell, the mRNA is translated into a protein.
You can see an animation of mRNA translation in this Youtube video.
The vaccine mRNA contains the genetic code for a slightly modified version of the SARS-Cov-2 spike protein (the protein that’s responsible for binding to the ACE2 receptor on our cells in order to gain entry and cause infection). In essence, the vaccine causes our own cells to manufacture a viral protein, which can then be recognized by our immune system. Immune cells then create new antibodies (which are also proteins), that recognize the viral protein. When an individual with antibodies encounters the actual virus, the antibodies bind to the virus and tag it for destruction by immune cells. This is the primary means by which the Moderna mRNA vaccine will generate immunity – by generating antibodies1:K. S. Corbett et al., “Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates,” N. Engl. J. Med., vol. 383, no. 16, pp. 1544–1555, Oct. 2020, doi: 10.1056/NEJMoa2024671. It also appears that there may be some T-cell mediated immunity from vaccination as well.
This particular vaccine requires two injections (3 or 4 weeks apart from one another) to ensure that a sufficient quantity of neutralizing antibodies are produced. Though it’s possible that some individuals will have sufficient immunity from a single dose, you won’t know it, and thus it’s likely that two doses will be recommended for all recipients.
Is it safe and how do we know?
The Moderna vaccine has been in development since January, and has been given to a diverse population of over 30,000 participants in clinical trials since March 16, with no severe adverse events documented thus far.
The manufacture of the first clinical batch was completed on Feb 7, 2020. The first participant in the first phase of clinical testing was dosed on March 16, 2020. On May 29, the second phase of clinical testing resulted in the recruitment of 300 people age 18-55, and another 300 over age 55. Phase three is a randomized placebo-controlled study of 30,000 participants over age 18, enrollment of which was completed on October 22, 2020. More than 7,000 of the participants are over age 65; 5,000 are under age 65 but have significant comorbid conditions (e.g. diabetes, obesity, cardiac disease); 11,000 participants are from “communities of color,” with 6,000 who “identify as Hispanic or LatinX,”; and over 3,000 who “identify as Black or African American”2:“Moderna’s COVID-19 Vaccine Candidate Meets its Primary Efficacy Endpoint in the First Interim Analysis of the Phase 3 COVE Study | Moderna, Inc.” Accessed: Jan. 06, 2021. [Online]. Available: https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy/.
One safety concern is the interaction of the vaccine with the immune system. Explicitly, some are concerned that antibodies produced as a result of vaccination could cause a subsequent Covid-19 infection to actually be more severe. One way this could happen is through a syndrome called “vaccine associated enhanced respiratory disease” (VAERD).
VAERD occurs when a vaccine recipient makes antibodies that bind to a viral protein, but that do not fully neutralize the virus. In this case, the virus, now bound to this antibody, could “hyper-activate” the immune system, so to speak. This “hyper-activation” could cause a more severe response to viral infection than would have occurred without vaccination.
According to researchers, this risk has been mitigated by ensuring the antibodies produced by vaccine recipients are “potently neutralizing,” and that Th2-biased CD4 T-cell responses are avoided3:K. S. Corbett et al., “Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates,” N. Engl. J. Med., vol. 383, no. 16, pp. 1544–1555, Oct. 2020, doi: 10.1056/NEJMoa2024671.
Is it effective and how do we know?
It appears that the vaccine is highly effective at preventing Covid-19 infection.
At a dose of 100 mcg, after 8 weeks, non-human primates were exposed directly to virus by the intranasal and the intratracheal route. This means that animals were given doses of virus into their noses and lungs. Seven days later, there was no measurable viral RNA or viral antigen within the respiratory tract of the vaccinated animals. The animals were then sacrificed. Researchers examined their lungs for signs of infection and inflammation – none was found. This means that vaccinated animals were able to clear the virus from their noses and lungs rapidly after exposure and that the virus did not leave any evidence of damage in its wake.
In addition to this animal experiment, human clinical trial data shows that neutralizing antibodies are produced in amounts equal to or greater than that produced by natural infection. This response was seen across age groups, including recipients over age 70 (the vaccine has not been tested in people under age 18).
Furthermore, in ongoing clinical trials, roughly one tenth of vaccinated humans have developed symptomatic Covid-19 infection in comparison to the placebo group.
Will it prevent transmission?
It will probably attenuate transmission significantly. It appears that viral replication in the nasopharynx is diminished in vaccinated non-human primates, suggesting that the vaccine may be very helpful in limiting transmission for at least three reasons: i) decreased viral replication, ii) decreased duration of viral carriage, iii) decreased number of infected individuals in a vaccinated population at a given time.
What are the “side effects,” from vaccination?
Based on phase 2 data, it appears as though many recipients will have at least one “mild,” or “moderate” symptom from vaccination. The reported symptoms will be familiar to almost everyone: headache, myalgia (i.e. body or muscle aches), arthralgia (i.e. joint aches), injection site pain, and fatigue. Very few recipients had fever or chills4:E. J. Anderson et al., “Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults,” N. Engl. J. Med., vol. 0, no. 0, p. null, Sep. 2020, doi: 10.1056/NEJMoa2028436.
I have seen anecdotes that the reaction to the second dose of vaccine in particular may be more significant than most people are accustomed to feeling with familiar vaccines such as the flu vaccine.
Will the vaccine be useful in those previously infected with Covid-19?
I haven’t seen any data or expert commentary to support this one way or the other. However, quantity of neutralizing antibody seems to be significantly higher in vaccine recipients compared to post-Covid patients who donated convalescent plasma. There has also been evidence of waning immunity months after infection. Thus, it follows that vaccination might be beneficial even for those previously infected.
Furthermore, researchers surmise that vaccination will confer improved immunity as compared to natural infection for several additional (and highly technical) reasons that you can read about here.
What is the onset and duration of immunity?
Based on animal and human data, a vaccine recipient will likely develop immunity by 6 or 7 weeks after the first of two injections5:K. S. Corbett et al., “Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates,” N. Engl. J. Med., vol. 383, no. 16, pp. 1544–1555, Oct. 2020, doi: 10.1056/NEJMoa2024671. is administered. The duration of immunity (i.e. the period of time that a vaccine recipient will be immune after vaccination) is currently unknown, but based on antibody data from natural infection, it’s reasonable to assume that vaccine generated immunity will last at least three months, but probably much longer (perhaps a year or two according to some experts). There are several reasons to believe that vaccine generated immunity will be more potent than immunity from natural infection.
Will I be taking it?
I will most likely take the vaccine, but not until at least two months after the vaccine has been rolled out – (point of clarification – two months after the delivery of the last dose in clinical trials).
I am adopting this strategy based on the interview of Paul Offit, MD, who appeared on Peter Attia’s Podcast several weeks ago. As an infectious disease and vaccine expert, and member of the FDA advisory board for the Covid-19 vaccine, Paul pointed out that for serious vaccine side effects that have occurred with other vaccines – Polio, Flu, Measles, and Yellow Fever vaccines – the severe adverse effects were discovered within two months of vaccine availability, but not necessarily before.
I highly recommend listening to Peter Attia’s podcast episode featuring Paul Offit, MD. In the interview, he provides fascinating historical context and detailed information about Covid-19 vaccination.
If I were at higher risk for severe Covid-19 (i.e. over age 65 and/or suffered from -comorbid conditions such as diabetes, hypertension, obesity, etc), then I may be more likely to take the vaccine as soon as humanly possible.
References: K. S. Corbett et al., “Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates,” N. Engl. J. Med., vol. 383, no. 16, pp. 1544–1555, Oct. 2020, doi: 10.1056/NEJMoa2024671. : “Moderna’s COVID-19 Vaccine Candidate Meets its Primary Efficacy Endpoint in the First Interim Analysis of the Phase 3 COVE Study | Moderna, Inc.” Accessed: Jan. 06, 2021. [Online]. Available: https://investors.modernatx.com/news-releases/news-release-details/modernas-covid-19-vaccine-candidate-meets-its-primary-efficacy/. : E. J. Anderson et al., “Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults,” N. Engl. J. Med., vol. 0, no. 0, p. null, Sep. 2020, doi: 10.1056/NEJMoa2028436.
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