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mRNA Vaccines

Last reviewed: August 23, 2021 

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The following is a curated review of key information and literature about this topic. It is not comprehensive of all data related to this subject. 

 

Overview and Mechanism 

mRNA vaccines contain messenger RNA (mRNA), a single-stranded RNA molecule that complements DNA. It is created in the nucleus, when DNA is transcribed by RNA polymerase to create pre-mRNA (Zipursky, 2000). Pre-mRNA is then spliced into mRNA, which is exported from the nucleus to the cytoplasm and “read” by ribosomes (the translation machinery of cells). Ribosomes then make proteins. 
 
mRNA vaccines use lab-created mRNA encapsulated within nanoparticles. Translation of the mRNA results in the development of a protein antigen that triggers an immune response (Schlake, 2012). mRNA vaccines deliver mRNA directly to the cytoplasm, where it is translated by ribosomes. The mRNA does not enter the nucleus and therefore cannot be incorporated into the genome. Its presence in the cell is transient, and it is quickly metabolized and eliminated via cellular processing mechanisms (Pardi, 2018). 

Unlike conventional vaccines, which can take months to produce, mRNA vaccines can be created quickly and are more easily scaled because they are based on an organism’s genetic code. 

The concept of mRNA vaccines was first developed in the early 1990s (Schlake, 2012). However, due to difficulty with the inherent instability of mRNA, as well as delivery challenges and other factors, the field did not make significant strides until the past decade, when technological advances and investment led to significant development. Prior to the COVID-19 pandemic, mRNA vaccines targeting infectious diseases including HIV-1, rabies, Zika and influenza were already in clinical trials, as were mRNA vaccines targeting multiple hematologic and solid organ malignancies (Pardi, 2018).  

Soon after the COVID-19 pandemic emerged, Pfizer and BioNTech began to develop a mRNA vaccine against SARS-CoV-2, as did Moderna — the latter in partnership with the National Institute of Allergy and Infectious Diseases. 

  • The Pfizer-BioNTech vaccine, BNT162b2, uses mRNA to create the receptor binding domain of the spike protein of SARS-CoV-2 (Walsh, 2020). The spike protein is what SARS-CoV-2 uses to attach to host cells and enter them. 
  • The Moderna vaccine, mRNA-1273, uses mRNA to create the SARS-CoV-2 spike protein stabilized in its prefusion conformation (Jackson, 2020). 

Studies of both vaccines have shown them to be highly effective in preventing symptomatic COVID-19, and safe after several months of follow-up. 

 

Efficacy 

Both the Pfizer-BioNTech and Moderna COVID-19 vaccines have proven to be highly effective against COVID-19 in post-authorization observational studies conducted in a variety of settings among diverse populations using a variety of clinical endpoints. However, there is accumulating evidence that their protective effect against infection may wane over time. In August 2021, CDC released a series of Morbidity & Mortality Weekly Reports with new long-term follow-up data about the Pfizer-BioNTech and Moderna COVID-19 vaccines' effectiveness. CDC has provided IDSA and its other partner organizations with the following summary: 

  • "Among fully vaccinated people in New York state (data includes NYC) from May 3–July 25, 2021, COVID-19 vaccines were more than 90% effective against hospitalizations (Tenforde, August 2021) 
    • A new study finds that among all adults in New York state, overall effectiveness against new COVID-19 infections declined from about 92% to about 80%.  
    • The decline in effectiveness against new infections coincides with the increase in the Delta variant in the United States, along with relaxation of masking and physical distancing recommendations.  
    • The factors driving the apparent changes in vaccine effectiveness, including variations by age, are uncertain. The substantially increased infectiousness of the Delta variant might underpin its increased transmissibility and could potentially lead to reduced vaccine-induced protection against infection. 
       
  • "The Pfizer and Moderna COVID-19 vaccines were highly effective in providing at least 24 weeks of protection for fully vaccinated adults against severe COVID-19 illness requiring hospitalization (Rosenberg, August 2021) 
    • Vaccine effectiveness against COVID-19 associated hospitalization was 86% during the first 2–12 weeks post-vaccination and 84% effective during the following 12-week period.  
    • The vaccine was found to be 90% effective against COVID-19 associated hospitalizations for people without immunocompromising conditions.  
    • For those with immunocompromising conditions, the vaccine was found to be only 63% effective against hospitalizations associated with COVID-19 (over the 24 week study). CDC now recommends that people whose immune systems are moderately to severely compromised should receive an additional dose of mRNA COVID-19 vaccine at least 4 weeks after their second dose, for a total of three doses. Widespread vaccination is a critical tool to reduce the risk of hospitalization due to COVID-19. 
       
  • "Nursing home residents who were prioritized for COVID-19 vaccination early in the U.S. vaccination program might be among the first groups to show evidence of potential waning of the immunity provided by vaccines (Nanduri, August 2021) 
    • Among nursing home residents, in the pre-Delta period two doses of mRNA vaccine were 75% effective against COVID-19 infections - but during the Delta period, mRNA vaccine effectiveness declined to 53%.  
    • Investigators could not determine if the lowered vaccine effectiveness was caused by potential waning immunity, reduced protection against the Delta variant (that became the dominant strain within 6 months after vaccine rollout), or a combination of both factors.
    • Vaccination of nursing home residents, staff members, and visitors should be prioritized because residents remain at higher risk for COVID-19 despite vaccination.  
    • A potential need for an additional vaccine dose exists among populations at higher risk of severe COVID-19 outcomes."

HHS has announced plans to offer eight-month booster shots beginning in September 2021 subject to FDA evaluation and recommendations from CDC's ACIP regarding the safety and effectiveness of a third dose. For information about the August 2021 FDA/CDC approval of an additional COVID-19 mRNA vaccine dose for certain immunocompromised populations, refer to our COVID-19 Vaccines in Immunocompromised Patients section.

 

Safety 

In post-authorization studies, both the Pfizer-BioNTech and Moderna COVID-19 vaccines have been demonstrated to be safe. The patterns of solicited local and systemic adverse reactions mirror those observed in the Phase 3 clinical trials of both vaccines. The only new safety signal identified in post-authorization studies is the incidence of acute allergic reactions, including anaphylaxis, following either vaccine, which were not observed in the Phase 3 trials. 

Acute Allergic Reactions to mRNA COVID-19 Vaccines (Blumenthal, March 2021). 

This prospective study invited Mass General Brigham employees who received a first dose of an mRNA COVID-19 vaccine to complete a symptom survey for 3 days after vaccination. Of 64,900 employees who received a first dose of vaccine, 40% (N=25,929) received the Pfizer-BioNTech COVID-19 vaccine and 60% (N=38,971) received the Moderna COVID-19 vaccine, with 81% (52,805) completing at least 1 symptom survey. Of these, 1,365 employees (2.1%) reported any allergic symptoms, and 16 (0.025%) reported anaphylaxis. Rates of allergic reaction were slightly higher with the Moderna COVID-19 vaccine (2.20% versus 1.95%, p=0.03). Nearly all cases of anaphylaxis were among women (N=15, 94%), nearly a third of whom (N=5, 31%) had a history of anaphylaxis. One anaphylaxis case required ICU admission, 9 received intramuscular epinephrine and all recovered without sequelae. Reported cases of anaphylaxis were confirmed with either Brighton Collaboration or NIAID/Food Allergy and Anaphylaxis Network criteria. 

 

First Month of U.S. COVID-19 Vaccine Safety Monitoring (Gee, February 2021). 

From Dec. 14, 2020-Jan. 13, 2021, data submitted to the Vaccine Adverse Events Reporting System and v-safe showed 13,794,904 doses of mRNA COVID-19 vaccines administered in the U.S., with 6,994 VAERS reports and 1,602,065 vaccine recipients who completed at least one v-safe survey. There were 113 deaths reported through VAERS, of which 78 (69%) occurred in long-term care facilities, more than half of these in hospice care or with do-not-resuscitate orders. Data on solicited local and systemic reactions from v-safe reports mirrored findings in clinical trials of the Pfizer-BioNTech and Moderna COVID-19 vaccines, with injection site pain, fatigue, headache, myalgia and chills being the most frequently reported events. These were more common in younger individuals for both vaccines and after the second dose of the Pfizer-BioNTech COVID-19 vaccine (the period of observation did not include second doses of the Moderna COVID-19 vaccine). Overall, there were no unexpected patterns of adverse reactions or safety concerns. 

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Immunogenicity 

The Pfizer-BioNTech and Moderna COVID-19 vaccines were demonstrated to elicit similarly robust immune responses against SARS-CoV-2 across patient populations in clinical trials. Post-authorization immunogenicity studies of these vaccines have focused on questions that may be relevant to vaccine implementation, including immune responses following a single dose of vaccine, specifically among individuals with a prior history of SARS-CoV-2 infection. 

Antibody Responses in Seropositive Persons After a Single Dose of SARS-CoV-2 mRNA Vaccine (Krammer, March 2021). 

This analysis of anti-SARS-CoV-2 spike IgG antibody responses to a single dose of a mRNA COVID-19 vaccine included a total of 110 individuals with or without documented pre-existing immunity to SARS-CoV-2. Of these, 67 participants were seronegative and 43 were seropositive, with a mean age of 40.0 years (range, 24-68). The majority of participants received the Pfizer-BioNTech COVID-19 vaccine (N=88, 80%), with the remainder (N=22, 20%) receiving the Moderna COVID-19 vaccine. Most seronegative individuals had low antibody titers for up to 12 days post-vaccination, whereas seropositive individuals had significantly higher titers within days (some within 4 days) after vaccination. Post-vaccination antibody titers among those with preexisting immunity were 10-45 times higher than in seronegative individuals at the same time points, even exceeding the antibody titers achieved by this group after the second dose of the vaccine by a factor of 6. Seropositive individuals demonstrated no further increase in antibody titers after the second dose of vaccine, compared with seronegative individuals whose titers increased by a factor of 3 after the second dose. 

 

Binding and Neutralization Antibody Titers After a Single Vaccine Dose in Health Care Workers Previously Infected With SARS-CoV-2 (Saadat, March 2021). 

This immunogenicity study used enzyme-linked immunosorbent assay to examine IgG antibody responses against SARS-CoV-2 spike trimer among 59 health care workers at University of Maryland Medical Center. The subjects were identified through serosurvey as seronegative (N=17), seropositive with asymptomatic COVID-19 (N=16) or seropositive with symptomatic COVID-19 (N=26). Investigators calculated reciprocal half-maximal binding titers (dilution of plasma that achieves 50% of maximal binding of a known control) at days 0, 7 and 14 after dose 1 of either the Pfizer-BioNTech (N=29) or Moderna (N=30) COVID-19 vaccine. At 0, 7 and 14 days, half-maximal titers were significantly higher among seropositive health care workers with either asymptomatic (208, 29364, 34033) or symptomatic (302, 32301, 35460) COVID-19, when compared with seronegative health care workers (<50, <50, 924). The authors also determined live virus neutralization titers at day 0 and 14, and these were each significantly higher among seropositive health care workers. 

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Pfizer-BioNTech COVID-19 Vaccine  

Overview

The vaccine, BNT162b2, was fully approved by FDA in August 2021. It had previously received emergency use authorization for use in individuals 12 years of age and older, and was the first COVID-19 vaccine authorized in the United States for emergency use.

For information about U.S. COVID-19 vaccine availability and prioritization, refer to our page on vaccine distribution
 

Literature 

 

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine (Polack, December 2020).  

Overall, in this interim analysis of a Phase 2/3 randomized placebo-controlled efficacy trial, BNT162b2 was effective at preventing symptomatic COVID-19 and was safe at a median time to follow-up of 2 months. 

Study population:  

  • BNT162b2 is an mRNA vaccine that is given in 2 doses, 21 days apart.   
  • In a Phase 2/3 multinational randomized placebo-controlled efficacy clinical trial, 43,538 participants over 16 years of age from 152 sites worldwide who were either healthy or had stable chronic medical conditions underwent 1:1 randomization.  
  • 43,448 received injections.  
  • 21,720 received 2 doses of BNT162b2, and 21,728 received a saline placebo.  
  • Patients with prior known COVID-19, on immunosuppressive therapy, who had an immunocompromising condition or who were pregnant were excluded. People with well-controlled HIV infection were included.  
  • This publication is an interim analysis of the trial; additional publications with longer time to follow-up and examining safety in specific groups are forthcoming. 
  • 3% of participants had serologic evidence of prior COVID-19 at the time of enrollment (but would have had asymptomatic disease, per enrollment exclusion criteria). 

Primary endpoints:  

  • Efficacy: The efficacy of BNT162b2 against confirmed COVID-19 with onset at least 7 days after the second dose in participants who had been without serologic or virologic evidence of SARS-CoV-2 infection up to 7 days after the second dose; efficacy in participants with and participants without evidence of prior infection.  
  • Confirmed COVID-19 was defined as having a positive RT-PCR respiratory specimen for SARS-CoV-2 AND at least one of the following: fever, new or increased cough, new or increased shortness of breath, chills, new or increased muscle pain, new loss of taste or smell, sore throat, diarrhea or vomiting. 
  • Safety: Solicited local or systemic adverse events and use of an antipyretic or pain medication within 7 days of receiving either the vaccine or placebo via an electronic diary in a “reactogenicity” subset of patients; unsolicited adverse events reported through 1 month after the second dose of vaccine; unsolicited adverse events through 6 months after the second dose.  
  • 196 people living with HIV were included in the trial, but their safety data are being analyzed separately and has not yet been reported.  
  • 2-month follow-up data were available for 37,706 participants; in the reactogenicity subset, data were available for 8,183 participants.  

Key findings:  

Efficacy  

  • As of the writing of the report, 36,523 participants with no serologic or virologic evidence of existing or prior SARS-CoV-2 infection could be evaluated for efficacy at least 7 days after the second dose.   
  • As of the writing of the report, 40,137 participants with and without prior infection could be evaluated at least 7 days after the second dose.  
  • At the time of analysis, 3,614 participants had serologic evidence of COVID-19.   
  • Per information shared with FDA, 1,747 people in the vaccinated group had positive serology for SARS-CoV-2, compared to 1,847 in the placebo group.  
  • In the 37,706 participants who had a median of at least 2 months of safety data available after the second dose:    
  • The median age was 52 years, and 42% of participants were older than 55 years.    
  • 83% were white, 9% were Black or African American and 28% were Hispanic or Latinx.    
  • 35% were obese (BMI>= 30.0 kg/m2), and 21% had at least one coexisting condition.    
  • Among 36,523 participants who had no serologic or virologic evidence of existing or prior SARS-CoV-2 infection, there were 8 cases of COVID-19 with onset at least 7 days after receiving the second dose of BNT162b2, and 162 cases with onset at least 7 days after receiving the second dose of placebo.  
  • BNT162b2 was 95% effective in preventing COVID-19 disease (95% CI, 90.3-97.6).    
  • Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index and the presence of coexisting conditions.    
  • Among the 40,137 participants with and without evidence of prior infection, 9 cases occurred with onset at least 7 days after receiving the second dose of BNT162b2 and 169 cases occurred with onset at least 7 days after receiving the second dose of placebo.    
  • BNT162b2 was 94.6% effective in preventing COVID-19 disease in this group (95% CI, 89.9-97.3).   
  • Of the 3,614 participants who had serologic evidence of COVID-19 at the time of analysis, there were 9 cases of COVID-19 disease in the placebo group and 10 in the vaccinated group.   
  • When examining rates of disease after the first dose of vaccine and before the second, there were 39 cases in the vaccinated group and 82 in the placebo group, resulting in a 52.4% efficacy rate after one dose (95% CI, 29.5-68.4).  

Safety  

  • The safety analysis included all participants who had received at least one dose of the vaccine or placebo.  
  • In the reactogenicity subset, among those aged 16-55 years:  
  • Approximately 93% of those who received BNT162b2 had mild-to-moderate pain, redness or swelling at the infection site after dose 1 and 88% experienced these symptoms after dose 2. Approximately 15% of these events occurred in the placebo group after dose 1 and 13% after dose 2. 
  • In the reactogenicity subset, among those aged 55 years or more:  
  • Approximately 82% of those who received BNT162b2 had mild-to-moderate pain, redness or swelling at the infection site after dose 1; 79% experienced these symptoms after dose 2. Approximately 11% of these events occurred in the placebo group after dose 1 and 9% after dose 2.  
  • In vaccine recipients, the most commonly-reported systemic events were fatigue and headache (59% after the first dose and 52% after the second dose among younger vaccine recipients, aged 16-55 years; 51% after the first dose and 39% after the second dose among older recipients, aged >55 years. 
  • Fatigue and headache were also reported by many placebo recipients (23% after the first dose and 24% after the second dose among younger vaccine recipients; 17% after the first dose and 14% after the second dose among older recipients).  
  • Fever (temperature ≥38 C) was reported after the second dose by 16% of younger vaccine recipients, and by 11% of older recipients.  
  • The incidence of serious adverse events was similar in the vaccine and placebo groups (0.6% and 0.5%, respectively).  
  • Among 21,621 people in the trial who received BNT162b2, four related serious adverse events were reported: shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia and right leg paresthesia.   
  • Four participants in the clinical trial who received the vaccine later developed Bell’s palsy. These cases occurred at 3, 9, 37 and 48 days after vaccination. The observed frequency of reported Bell’s palsy in the vaccine group is consistent with the expected background rate in the general population, according to the FDA. 
  • No deaths were considered by the investigators to be related to the vaccine or placebo.    

Limitations:  

  • The report includes 2 months of follow-up after the second dose of the vaccine for only half of the trial participants.   
  • Due to the high efficacy found in the trial, the original plan of following placebo recipients for 2 years will not be followed due to ethical concerns. Therefore, there will be no placebo group with which to assess long-term efficacy and safety.   
  • The primary efficacy endpoint was clinical disease; asymptomatic infection was not assessed, although additional data utilizing a serologic endpoint are being collected. 
  • The trial did not include children, immunocompromised people or pregnant women, but trials are being developed to assess BNT162b2 in these groups.  
  • While there was a small group of people with evidence of prior COVID-19 infection at the time of analysis, the number of cases in this group was too small to draw any conclusions about the efficacy of the vaccine in individuals with prior infection; this may change as the trial continues. 
  • Serial RT-PCR testing was not performed, and so the efficacy of the vaccine in potentially preventing spread of SARS-CoV-2 could not be determined.  

 

Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients (Amit, March 2021). 

Observational study of 9,647 health care workers at Israel’s largest hospital system after rollout of Israel’s Pfizer-BioNTech COVID-19 vaccination campaign. All health care workers engaged in daily symptom reporting and immediate same-day testing for SARS-CoV-2 if indicated/desired. Investigators calculated vaccine-associated reductions in rate of SARS-CoV-2 infection among health care workers starting 15 days after the first dose, using the number of days each health care worker was unvaccinated and the first 14 days after the first dose as “unvaccinated” or control follow-up time. Between Dec. 19, 2020 and Jan. 24, 2021, there were 170 SARS-CoV-2 infections (58% symptomatic, 42% asymptomatic) detected in the study population, of which 89 (52%) occurred in those who were unvaccinated, 78 (46%) in those who had received one dose and 3 (2%) in those who had received both doses. This amounted to an 85% (95% CI, 71-92) adjusted rate reduction in symptomatic SARS-CoV-2 infections during days 15-28 after the first dose, and a 75% (95% CI, 72-84) adjusted rate reduction in all SARS-CoV-2 infections (i.e., including asymptomatic infections detected through contact tracing) during days 15-28 after the first dose.  

 

Effectiveness of BNT162b2 mRNA Vaccine Against Infection and COVID-19 Vaccine Coverage in Healthcare Workers in England, Multicenter Prospective Cohort (SIREN) Study (Hall, February 2021 - pre-print; not peer reviewed). 

The goal of this prospective cohort study of U.K. health care workers and support staff was to evaluate the effectiveness of that country’s vaccination roll-out, including its decision to permit a delay of up to 12 weeks in administrating the second dose of authorized COVID-19 vaccines. A total of 29,378 participants enrolled in the study, of whom 23,324 workers from 104 hospitals were included in the analysis. This cohort included 8,203 individuals (35%) with a prior history of SARS-CoV-2 infection (prior positive antibody or PCR, or seropositive at baseline) and 15,121 (65%) with no history of infection. A majority of the cohort was female (N=19,692, 84%), under age 65 (N=22,955, 98%) and without underlying medical conditions (N=17,450, 75%). By the end of the study period, vaccine coverage in the cohort had reached 89%, with 94% (N=19,384) of vaccinated cohort members receiving the Pfizer-BioNTech COVID-19 vaccine and the remainder receiving the Oxford-AstraZeneca COVID-19 vaccine. Only 1,607 (8%) received both doses by the end of the study follow-up period. Vaccine effectiveness against SARS-CoV-2 infection starting 21 days after the first dose of Pfizer-BioNTech COVID-19 vaccine was 70% (95% CI, 53-87), which increased to 85% (95% CI, 74-96) starting 7 days after the second dose. There were 51 asymptomatic infections in the unvaccinated cohort compared with 10 in the vaccinated cohort, suggesting protection against asymptomatic infection. 

 

Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine (Skowronski, February 2021). 

Researchers analyzed FDA submission data to derive the efficacy of the Pfizer-BioNTech COVID-19 vaccine during the period beginning 7 days after dose 1 (when immunity is expected to begin to develop) and ending at dose 2. Between 7 and 14 days after the first dose, vaccine efficacy was 68.5% (95% CI, 46.5-81.5), and from 14 days after dose 1 until dose 2, vaccine efficacy was 92.6% (95% CI, 69.0-98.3). This efficacy estimate was similar to the single-dose estimate starting 14 days after dose 1 computed for the Moderna COVID-19 vaccine, as reported in its FDA briefing document. 

 

BNT162b2 mRNA COVID-19 Vaccine in a Nationwide Mass Vaccination Setting (Dagan, February 2021). 

This observational study of the impact of Israel’s Pfizer-BioNTech COVID-19 vaccination campaign on COVID-19 outcomes uses data from one of the country’s four integrated health services. Investigators matched 596,618 vaccinated individuals with no prior history of SARS-CoV-2 infection, age 16 or older, to unvaccinated controls in a 1:1 fashion. Matching was based on variables that may be associated with vaccination or the risk of SARS-CoV-2 infection. The study excluded populations with high variability in likelihood of exposure or COVID-19 outcomes, including health care workers. Researchers measured effectiveness using outcomes including detection of SARS-CoV-2 by PCR, symptomatic infection, hospitalization, severe illness and death, starting 14 days after dose 1. From 14 to 20 days after dose 1, vaccine effectiveness was 46% against SARS-CoV-2 infection (95% CI, 40 to 51); 57% against symptomatic COVID-19 (95% CI, 50 to 63); 74% against hospitalization (95% CI, 56 to 86); 62% against severe illness (95% CI, 39 to 80); and 72% against death (95% CI, 19 to 100). In the follow-up period starting 7 days after dose 2, vaccine effectiveness was 92% against infection (95% CI, 88 to 95); 94% against symptomatic illness (95% CI, 87 to 98); 87% against hospitalization (95% CI, 55 to 100); and 92% against severe disease (95% CI, 75 to 100). 

 

Safety and Immunogenicity of Two RNA-Based COVID-19 Vaccine Candidates (Walsh, December 2020).  

Placebo-controlled, observer-blinded, dose-escalation, Phase 1 trial conducted in the United States to assess the safety and immunogenicity of three dose levels of BNT162b1 and BNT162b2. A group of 195 healthy adults 18-55 years of age and those 65-85 years of age were randomly assigned to receive either placebo or BNT162b1 or BNT162b2. Trial groups were defined according to vaccine candidate, age of the participants and vaccine dose level (10 μg, 20 μg, 30 μg and 100 μg). BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1, particularly in older adults. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2–neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. 

 

Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine (CDC COVID-19 Response Team, January 2021). 

From Dec. 14-23, 2020, data from 1,893,360 first doses of the Pfizer-BioNTech COVID-19 vaccine in the U.S. were submitted to the Vaccine Adverse Events Reporting System. Among the 1,893,360 first doses, there were 175 cases of possible allergic reactions CDC identified for review, of which 21 (12%) met the Brighton Collaboration case definition criteria for anaphylaxis. Most of these were in women (n=19, 90%) and median time to onset of symptoms was 15 minutes. Four of the cases required hospitalization, while 17 were managed in the emergency department. Most of the cases of anaphylaxis had a documented history of allergies to drugs, foods or insect stings (n=17, 81%), and 7 (33%) had previously experienced anaphylaxis. The 83 non-anaphylaxis reactions were also predominantly in women (90%), with a 12-minute median interval to symptom onset. These reactions included pruritus, rash, itchy and scratchy sensations in the throat and mild respiratory symptoms. 

 

Impact of age, ethnicity, sex and prior infection status on immunogenicity following a single dose of the BNT162b2 mRNA COVID-19 vaccine: real-world evidence from health care workers, Israel, December 2020 to January 2021 (Abu Jabal, February 2021). 

This analysis measured anti-spike IgG antibody levels 21 days after dose 1 of the Pfizer-BioNTech COVID-19 vaccine in 514 health care workers at a single medical center in Israel. Of the subjects, 17 (3.3%) had prior evidence of SARS-CoV-2 infection (6 with a positive IgG at baseline and 11 who were IgG negative but had a history of positive PCR test for SARS-CoV-2). Those with prior infection mounted significantly higher post-vaccination anti-spike IgG levels compared to those with no history of SARS-CoV-2 infection (geometric mean concentration of 61.5 vs. 573). This was true regardless of baseline antibody status and did not vary based on time since positive PCR test among those with a history of PCR-confirmed infection. 

 

Safety 

For up-to-date Pfizer-BioNTech COVID-19 vaccine safety considerations, refer to the Contraindications and Precautions section of CDC’s Interim Clinical Considerations for Use of COVID-19 Vaccines

 

Dosing & Administration  

The Pfizer-BioNTech COVID-19 vaccination series consists of 2 intramuscular doses given 3 weeks apart. 

Second doses administered within a grace period of ≤4 days from the recommended date for the second dose are considered valid; however, doses administered earlier do not need to be repeated. The second dose should be administered as close to the recommended interval as possible. However, there is no maximum interval between the first and second dose for either vaccine.  

The Pfizer COVID-19 vaccine is not interchangeable with other COVID-19 vaccines to complete the vaccination series. The safety and efficacy of a mixed-product series have not been evaluated. Both doses of the series should be completed with the Pfizer COVID-19 vaccine. However, if two doses of different mRNA COVID-19 vaccine products are inadvertently administered, no additional doses of either product are recommended at this time. 

Overall vaccine efficacy after one dose has not been studied. While there were patients in Phase 3 trials who received one dose and vaccine efficacy was reported in these patients, the overall number of such patients was small and they were only followed for a short time period. The duration and degree of their immune responses to the single dose of the vaccine is not known; until such data are available and the efficacy of one dose has been studied, FDA recommends that all recipients of the Pfizer-BioNTech COVID-19 vaccine complete a two-dose series

 

 

 

Moderna COVID-19 Vaccine  

Overview 

Moderna’s COVID-19 vaccine is an mRNA vaccine that has been shown to be highly effective in preventing symptomatic COVID-19. The vaccine, mRNA-1273, received emergency use authorization from the U.S. Food and Drug Administration in December 2020 for use in individuals 18 years of age and older, making it the second COVID-19 vaccine authorized in the United States. 

 

Literature 

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine (Baden, December 2020). 

Overall, in this Phase 3 randomized, stratified, double-blind, placebo-controlled trial, mRNA-1273 was effective at preventing symptomatic COVID-19 and was safe at a median time to follow-up of 2 months.   

Study population:  

  • mRNA-1273 is an mRNA vaccine that is given in 2 doses, 29 days apart.  
  • mRNA-1273-P301 is a Phase 3 ongoing randomized, stratified, double-blind, placebo-controlled trial.  
  • 30,420 participants over 18 years of age from 99 sites in the United States were randomized in a 1:1 manner to receive injections of either the mRNA-1273 (N=15,210) or a saline placebo (N=15,210) on day 1 and day 29.  
  • More than 96% of participants received both injections. 
  • 66.3% of the study population was comprised of patients 18-64 years of age with risk for progression to severe COVID-19, and patients >=65 years of age.    
  • Patients were considered to have risk for severe disease if they had any of the following comorbidities: diabetes, chronic lung disease, severe obesity, significant cardiovascular disease, liver disease or well-controlled HIV (persons with poorly controlled HIV were not included in the trial). 
  • There were 179 patients living with HIV in the trial; data on this specific group have not yet been reported.   
  • The mean age of the participants was 51.4 years, 47.3% of the participants were female, 24.8% were >=65 years of age and 16.7% were younger than 65 years of age and had predisposing medical conditions that put them at risk for severe COVID-19.  
  • The majority of participants were white (79.2%); 10.2% of participants were African American and 20.5% were Hispanic/Latinx.  
  • Patients had a negative SARS-CoV-2 status at baseline (with a negative RT-PCR and negative serology against the SARS-CoV-2 nucleocapsid at day 1).    
  • 2.2% of study participants had serologic evidence of prior COVID-19.  
  • Participants were excluded if they were pregnant or breastfeeding, pediatric, immunocompromised or had a known history of SARS-CoV-2.  
  • The interim primary efficacy analysis was based on the Per-Protocol Set, which consisted of 28,207 participants with negative baseline SARS-CoV-2 status and who received 2 doses of investigational product per schedule with no major protocol deviations.  
  • The set included 14,134 patients in the vaccine group and 14,073 patients in the placebo group.  

Primary endpoints:  

  • Efficacy: The reduction of incidence of COVID-19 among participants without evidence of SARS-CoV-2 infection before the first dose of vaccine in the period after 14 days post-dose 2.  
  • The case definition of confirmed COVID-19 was:   
    • At least 2 of the following systemic symptoms: Fever (>38 C), chills, myalgia, headache, sore throat, new olfactory and taste disorder(s) or at least 1 of the following respiratory signs/symptoms: cough, shortness of breath or difficulty breathing, OR clinical or radiographic evidence of pneumonia; and  
    • Nasopharyngeal swab, nasal swab or saliva sample (or respiratory sample, if hospitalized) positive for SARS-CoV-2 by RT-PCR.  
  • Safety: To describe the safety of mRNA-1273 after 1 or 2 doses.    
  • Solicited events: participants recorded local reactions, systemic events and antipyretic/pain medication usage from day 1 through day 7 after each dose.  
  • Unsolicited adverse events were collected from dose 1 to 28 days after the last dose.   
  • Medically attended adverse events and serious adverse events were also collected from dose 1 to the end of the study.  

Key findings:  

Efficacy  

  • Risk and demographics at baseline were reported in N=15,181 individuals receiving the vaccine and N=15,170 receiving placebo.   
  • At least one high-risk condition for severe COVID-19 was present in 27.1% of participants.   
  • There were no differences in demographics in the vaccine and placebo groups.   
  • As of Nov. 25, 2020, the participants had a median follow-up duration of 64 days (range, 0-97) after the second dose, with 61% of participants having more than 56 days of follow-up.  
  • After day 1 and through Nov. 25, 2020, a total of 269 COVID-19 cases were identified, with an incidence of 79.8 cases per 1,000 person-years (95% CI, 70.5 to 89.9) among participants in the placebo group with no evidence of previous SARS-CoV-2 infection. Subgroup analyses of the primary efficacy endpoint showed similar efficacy across age groups, genders, racial and ethnic groups and participants with medical comorbidities associated with high risk of severe COVID-19.   
  • For the primary analysis, 196 cases of COVID-19 were diagnosed: 11 cases in the vaccine group (3.3 per 1,000 person-years; 95% CI, 1.7 to 6.0) and 185 cases in the placebo group (56.5 per 1,000 person-years; 95% CI, 48.7 to 65.3), indicating 94.1% efficacy of the mRNA-1273 vaccine (95% CI, 89.3 to 96.8%; p<0.001) for the prevention of symptomatic SARS-CoV-2 infection as compared with placebo.   
  • Findings were similar across key secondary analyses including assessment starting 14 days after dose 1 (225 cases with placebo vs. 11 with mRNA-1273, indicating a vaccine efficacy of 95.2% [95% CI, 91.2 to 97.4]) and assessment including participants who were SARS-CoV-2 seropositive at baseline in the per-protocol analysis (187 cases with placebo, vs. 12 with mRNA-1273; one volunteer assigned to receive mRNA-1273 was inadvertently given placebo), indicating a vaccine efficacy of 93.6% (95% CI, 88.6 to 96.5).   
  • Between days 1 and 42, 7 cases of COVID-19 were identified in the mRNA-1273 group, as compared with 65 cases in the placebo group.  
  • A key secondary endpoint evaluated the efficacy of mRNA-1273 at preventing severe COVID-19.    
  • 30 participants in the trial had severe COVID-19; all 30 were in the placebo group (indicating vaccine efficacy of 100% [95% CI, could not be estimated to 1.0]), and one death among these participants was attributed to COVID-19.  
  • Among participants who were positive for SARS-CoV-2 by serologic or virologic testing at baseline (337 in the placebo group and 343 in the mRNA-1273 group), 1 case of COVID-19 was diagnosed by RT-PCR testing in a placebo recipient and no cases were diagnosed in mRNA-1273 recipients.   
  • Among participants who were negative for SARS-CoV-2 at baseline (by RT-PCR or antibody testing), in addition to symptomatic COVID-19 cases 39 (0.3%) in the placebo group and 15 (0.1%) in the mRNA-1273 group had nasopharyngeal swabs that were positive for SARS-CoV-2 by RT-PCR at the second dose visit (surveillance swab) but had no evidence of COVID-19 symptoms.  

Safety  

  • Safety data at the time of the interim analysis were available for 30,347 participants, with a median follow-up of 2 months. 
  • Solicited adverse events at the injection site occurred more frequently in the mRNA-1273 group than in the placebo group after both the first dose (84.2% vs. 19.8%) and the second dose (88.6% vs. 18.8%). 
  • In the mRNA-1273 group, injection-site events were mainly grade 1 or 2 in severity and lasted a mean of 2.6 and 3.2 days after the first and second doses, respectively.  
  • The most common injection-site event was pain after injection (86.0%). 
  • Delayed injection-site reactions (those with onset on or after day 8) were noted in 244 participants (0.8%) after the first dose and in 68 participants (0.2%) after the second dose. 
  • Reactions were characterized by erythema, induration and tenderness, and they resolved over the following 4 to 5 days. 
  • Solicited systemic adverse events occurred more often in the mRNA-1273 group than in the placebo group after both the first dose (54.9% vs. 42.2%) and the second dose (79.4% vs. 36.5%).  
  • The severity of the solicited systemic events increased after the second dose in the mRNA-1273 group, with an increase in proportions of grade 2 events (from 16.5% after the first dose to 38.1% after the second dose) and grade 3 events (from 2.9% to 15.8%). 
  • Solicited systemic adverse events in the mRNA-1273 group lasted a mean of 2.6 days and 3.1 days after the first and second doses, respectively. 
  • Both solicited injection-site and systemic adverse events were more common among younger participants (18 to <65 years of age) than among older participants (≥65 years of age). 
  • Solicited adverse events were less common in participants who were positive for SARS-CoV-2 infection at baseline than in those who were negative at baseline. 
  • The frequency of unsolicited adverse events, unsolicited severe adverse events and serious adverse events reported during the 28 days after injection was generally similar among participants in the two groups. 
  • 3 deaths occurred in the placebo group (one from intraabdominal perforation, one from cardiopulmonary arrest and one from severe systemic inflammatory syndrome in a participant with chronic lymphocytic leukemia and diffuse bullous rash) and 2 in the vaccine group (one from cardiopulmonary arrest and one by suicide). 
  • The frequency of grade 3 adverse events in the placebo group (1.3%) was similar to that in the vaccine group (1.5%), as were the frequencies of medically attended adverse events (9.7% vs. 9.0%) and serious adverse events (0.6% in both groups). 
  • Hypersensitivity reactions were reported in 1.5% and 1.1% of participants in the vaccine and placebo groups, respectively. 
  • Bell’s palsy occurred in the vaccine group (3 participants [<0.1%]) and the placebo group (1 participant [<0.1%]) during the observation period of the trial (more than 28 days after injection). 
  • No evidence of vaccine-associated enhanced respiratory disease was noted, and fewer cases of severe COVID-19 or any COVID-19 were observed among participants who received mRNA-1273 than among those who received placebo. 
  • Adverse events that were deemed by the trial team to be related to the vaccine or placebo were reported among 4.5% of participants in the placebo group and 8.2% in the mRNA-1273 group.  
  • The most common treatment-related adverse events (those reported in at least 1% of participants) in the placebo group and the mRNA-1273 group were fatigue (1.2% and 1.5%) and headache (0.9% and 1.4%). 
  • In the overall population, the incidence of treatment-related severe adverse events was higher in the mRNA-1273 group (71 participants [0.5%]) than in the placebo group (28 participants [0.2%]).  
  • The relative incidence of these adverse events according to vaccine group was not affected by age.  

Limitations:  

  • The primary efficacy endpoint was clinical disease; asymptomatic infection was not assessed, although additional data utilizing a serologic endpoint are being collected.  
  • The trial did not include children, immunocompromised people or pregnant women, but trials are being developed to assess mRNA-1273 in these groups.   
  • While there was a small group of people with evidence of prior COVID-19 infection at the time of analysis, the number of cases in this group was too small to draw any conclusions about the efficacy of the vaccine in individuals with prior infection; this may change as the trial continues.  
  • Serial RT-PCR testing was not performed, and so the efficacy of the vaccine in potentially preventing spread of SARS-CoV-2 could not be determined.   

 
Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults (Anderson, December 2020).  

In this Phase 1 open-label trial of mRNA-1273 in 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years), participants were assigned sequentially to receive two doses of either 25 μg or 100 μg of vaccine administered 28 days apart. Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. By day 57, among the participants who received the 25-μg dose, the anti–S-2P geometric mean titer was 323,945 among those between the ages of 56-70 years and 1,128,391 among those who were >=71 years of age; among the participants who received the 100-μg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18-55 years. 

Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19 (Doria-Rose, April 2021).  

In this Phase 1 open-label trial of mRNA-1273 in 33 healthy adults who received two injections of the vaccine 28 days apart, at a 209 day time point, geometric mean titers were: 92,451 (95% CI, 57,148 to 149,562) in participants 18 to 55 years of age; 62,424 (95% CI, 36,765 to 105,990) in those 56 to 70 years of age; and 49,373 (95% CI, 25,171 to 96,849) in those 71 years of age or older. Serum neutralizing antibodies continued to be detected in nearly all the participants at day 209. The estimated half-life of binding antibodies starting 14 days after dose 2 (using an exponential decay model, which assumes a steady decay rate over time) was 52 days (95% CI, 46-58), and for neutralizing antibodies (using a power-law model, which assumes a decreasing decay rate over time) it was 173 days (95% CI, 144-225) for pseudovirus neutralization and 202 days (95% CI, 159-272) for live-virus neutralization.  

 
Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination (Widge, December 2020).  

In this Phase 1 open-label trial of mRNA-1273 in 34 healthy adults who received two injections of the vaccine 28 days apart, at a 119 day time point, geometric mean titers were: 235,228 (95% CI, 177,236 to 312,195) in participants 18 to 55 years of age; 151,761 (95% CI, 88,571 to 260,033) in those 56 to 70 years of age; and 157,946 (95% CI, 94,345 to 264,420) in those 71 years of age or older. Serum neutralizing antibodies continued to be detected in all the participants at day 119. On a pseudovirus neutralization assay, the 50% inhibitory dilution geometric mean titer was 182 (95% CI, 112 to 296) in participants who were 18 to 55 years of age, 167 (95% CI, 88 to 318) in those 56 to 70 years of age and 109 (95% CI, 68 to 175) in those 71 years of age or older. 

An mRNA Vaccine Against SARS-CoV-2 — Preliminary Report (Jackson, November 2020)In this Phase 1 dose-escalation, open-label trial of mRNA-1273 in 45 healthy adults who received 2 doses of the vaccine 28 days apart, after 1 dose of the vaccine antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer, 40,227 in the 25-μg group, 109,209 in the 100-μg group and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719 and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected in all participants. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events. 

 

 

Safety 

For up-to-date Moderna COVID-19 vaccine safety considerations, refer to the Contraindications and Precautions section of CDC’s Interim Clinical Considerations for Use of COVID-19 Vaccines

 

 

Dosing & Administration

The Moderna COVID-19 vaccination series consists of 2 intramuscular doses, 0.5 mL each, given 4 weeks apart.  

Second doses administered within a grace period of ≤4 days from the recommended date for the second dose are considered valid; however, doses administered earlier do not need to be repeated. The second dose should be administered as close to the recommended interval as possible. However, there is no maximum interval between the first and second dose for either vaccine.  

The Moderna COVID-19 vaccine is not interchangeable with other COVID-19 vaccines to complete the vaccination series. The safety and efficacy of a mixed-product series have not been evaluated. Both doses of the series should be completed with the Moderna COVID-19 vaccine. However, if two doses of different mRNA COVID-19 vaccine products are inadvertently administered, no additional doses of either product are recommended at this time. 

Overall vaccine efficacy after one dose has not been studied. While there were patients in Phase 3 trials who received one dose and vaccine efficacy was reported in these patients, the overall number of such patients was small and they were only followed for a short time period. The duration and degree of their immune responses to the single dose of the vaccine is not known; until such data are available and the efficacy of one dose has been studied, FDA recommends that all recipients of the Moderna COVID-19 vaccine complete a two-dose series

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