1 INTRODUCTION

As of August 2021, there are three vaccines available in the United States for the prevention of coronavirus disease 2019 (COVID-19), the pandemic caused by severe acute respiratory syndrome virus 2 (SARS-CoV-2), BNT162b2 (Pfizer, Inc./BioNTech), mRNA-1273 (Moderna, Inc.), and Ad26.COV2.S (Johnson and Johnson/Janssen Global Services, LLC). These vaccines have the potential to dramatically reduce the number of COVID-19 cases and end the pandemic. Prior to their introduction into clinical practice, these vaccines underwent rigorous evaluation at the preclinical and clinical level. In the first months of their use in clinical practice, numerous studies have augmented our understanding of the safety and effectiveness of these agents. The purpose of this review is to summarize the approval process, clinical trial data, and early real-world experience with the COVID-19 vaccines currently authorized for use in the United States. It is important to note that this review is written in the context of vaccines available in the United States and that other vaccine products exist in other countries or may become available at a later date.

2 EMERGENCY USE AUTHORIZATION PROCESS

Prior to being available for routine clinical use, BNT162b2, mRNA-1273, and Ad26.COV2.S, each underwent review by the United States Food and Drug Administration (FDA) using the Emergency Use Authorization (EUA) mechanism. If a drug receives an EUA, the FDA may allow the use of unapproved medical products, such as the COVID-19 vaccine, if certain criteria are met which include no adequate, approved, and available alternatives.1

Specific to vaccine EUA, all safety data collected from phase 1 and 2 vaccine studies must be submitted and safety data from phase 3 studies must include a minimum of 2-month follow-up data for at least half of the study population.1 Furthermore, at least 3000 vaccine recipients must be followed for at least 1 month after completion of the full vaccine schedule to assess all clinical and serious adverse events. In addition to demonstrating efficacy, the point estimate for efficacy must be ≥50% and the lower-bound of the appropriately adjusted confidence interval must be >30%.2

While the review is being performed, the FDA holds a public meeting with the Vaccines and Related Biological Products Advisory Committee (VRBPAC) to discuss safety and efficacy and provide the public and scientific communities with data on whether to authorize a vaccine for EUA. Unlike the full FDA approval process which requires extensive data for approval based on preclinical, Phase 1, Phase 2, and Phase 3 clinical trials, an EUA is granted using the best available evidence during an emergency period of time. EUAs allow immediate access to a given therapy with the caveat that an EUA can be revised or revoked based on future safety or efficacy data. In the case of BNT162b2, mRNA-1273, and Ad26.COV2.S, each EUA was based on preclinical through Phase 3 data (see Clinical Trial Data).

It is critically important for clinicians to be able to articulate the difference between EUA and full FDA approval to patients because lack of understanding within the general public may be a considerable source of vaccine hesitancy among those that are unvaccinated. Specifically, according to a study conducted by the Kaiser Family Foundation, 31% of individuals surveyed reported they would be more inclined to receive the COVID-19 vaccine if one of the vaccines authorized under EUA received full FDA approval.3 These data demonstrate the importance of educating those who remain unvaccinated on the differences between EUA and FDA approval.

3 CLINICAL TRIAL DATA

BNT162b2, mRNA-1273, and Ad26.COV2.S, each has received EUA (and full approval for BNT162b2) in the United States based on the totality of the data reviewed by the FDA. Each vaccine was evaluated in double-blind, randomized, placebo-controlled clinical trials for safety and efficacy. These studies each enrolled tens of thousands of participants with similar baseline characteristics.4-6 For BNT162b2 and mRNA-1273, the primary efficacy endpoint was vaccine efficacy calculated as 100 × (1 – [attack rate with the vaccine]/[attack rate with the placebo]).4, 5 In contrast, vaccine efficacy for Ad26.COV2.S COVID-19 vaccine was calculated by [(1 – ratio (vaccine/placebo) of cumulative incidence by time t) × 100%].6

3.1 BNT162b2 mRNA COVID-19 vaccine (Pfizer/BioNTech)

BNT162b2 was evaluated in a two-dose vaccine series administered intramuscularly 21 days apart. Data for 37,706 participants met a cutoff date of October 9, 2020 to have at least 2 months of available safety data after the second dose of vaccine.4 The primary efficacy endpoints evaluated confirmed cases of COVID-19 (defined as positive nucleic acid amplification test [NAAT] for SARS-CoV-2 with COVID-19 symptoms, Table 1) within 7 days after the second dose and in participants with or without prior SARS-CoV-2. The primary safety endpoints were development of adverse events (local or systemic) and use of an antipyretic or pain medication within 7 days of each vaccine dose or placebo.

TABLE 1. Late-stage clinical trials of COVID-19 vaccines (BNT162b2, mRNA-1273, and Ad26.COV2.S) with emergency use authorization Vaccine Time and locations Study design Key inclusion criteria Key exclusion criteria Study population Outcomes Efficacy Safety BNT162b2 mRNA COVID-19 Vaccine (BioNTech and Pfizer)4 July 27, 2020–November 14, 2020 First data cutoff October 9, 2020 152 sites worldwide Phase 2/3 Randomized (1:1), placebo-controlled, observer-blinded N = 43,448 Age 16–85 years Healthy as judged by medical history, physical examination, and clinical judgment of investigator Immunosuppressive therapy Immunocompromising condition (HIV, HCV, and HBV) Persons who were pregnant or breastfeeding History of severe adverse reaction associated with a vaccine and/or severe allergic reaction (eg, anaphylaxis) to any component of the study intervention(s) Female: 49% White: 83% Black: 9% Hispanic/Latinx: 28% Median age: 52 years (42% >55 years) Primary Efficacy Outcome: COVID-19a at least 7 days after second injection in those without prior history of infection and those with and without prior history of infection Without prior evidence of infection: o Vaccine: 8 cases in 2214 person-years o Placebo: 162 cases in 2222 person-years o VE: 95.0% (90.3–97.6) With and without prior evidence of infection o Vaccine: 9 cases in 2332 person-years o Placebo: 169 cases in 2345 person-years o VE (95% CI): 94.6% (89.9–97.3) Severe COVID-19 after Dose 1 o Vaccine: 1/21,669 o Placebo: 9/21,686 o VE (95% CI): 88.9 (20.1, 99.7) No COVID-19-associated deaths observed

Local adverse events (V vs. P)b

Dose 1 o Pain: 78% vs. 12% o Redness: 5% vs. 1% o Swelling: 6% vs. 1% Dose 2 o Pain: 73% vs. 10% o Redness: 6% vs. 1% o Swelling: 7% vs. 0%

Systemic Adverse Events (V vs. P)

Dose 1 o Fever: 3% vs. 1% o Fatigue: 42% vs. 29% o Headache: 35% vs. 27% Dose 2 o Fever: 16% vs. 1% o Fatigue: 59% vs. 23% o Headache: 52% vs. 24%

mRNA-1273 SARS-CoV-2 Vaccine (Moderna) (COVE study)5

July 27, 2020–October 23, 2020 99 sites across the US Phase 3 Randomized (1:1), placebo-controlled, observer-blinded N = 30,420 Age ≥ 18 years No history of SARS-CoV-2 Persons deemed high risk of SARS-CoV-2 Healthy/stable chronic medical conditions Acutely ill or febrile 72 h prior to screening Persons who were pregnant or breastfeeding Known history of SARS-CoV-2 Allergy, anaphylaxis, urticaria, or other significant adverse reaction to the vaccine or its excipients Certain bleeding disorders Non-study vaccine requiring separation from COVID-19 vaccine Immunosuppressive or immunodeficient state, asplenia, recurrent severe infections Systemic immunosuppressants or immune-modifying drugs for >14 days within 6 months Immunoglobulin or blood products in the past 3 months Donated ≥450 ml of blood products within past 28 days Female: 47% White: 79% Black: 10% Hispanic/latinx: 21% Median age: 51 years (25% >65 years) Primary efficacy outcome: COVID-19 at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2 o Vaccine: 3.3 per 1000 person-years o Placebo: 56.5 cases per 1000 person-years o VE (95 CI%): 94.1% (89.3%–96.8%) Severe COVID-19 starting 14 days after second injection: o Vaccine: 0/14,134 o Placebo: 30/14,073 o VE (95% CI) based on hazard ratio: 1.00 (NE – 1.00) Severe COVID-19 starting 14 days after second injection: o Vaccine: 0/14,134 o Placebo: 30/14,073 o VE (95% CI) based on hazard ratio: 1.00 (NE – 1.00) Death o Vaccine: 2 (one from cardiopulmonary arrest and one by suicide) o Placebo: 3 (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)

Local adverse events (V vs. P)d

Dose 1 o Pain: 84% vs. 18% o Redness: 3% vs. 0% o Swelling: 6% vs. 0% Dose 2 o Pain: 88% vs. 17% o Redness: 9% vs. 0% o Swelling: 12% vs. 0%

Systemic adverse events (V vs. P)

Dose 1 o Fever: 1% vs. 0% o Fatigue: 37% vs. 27% o Headache: 33% vs. 27% Dose 2 o Fever: 16% vs. 0% o Fatigue: 65% vs. 23% o Headache: 59% vs. 23%

Ad26.COV2.S COVID-19 Vaccine (Johnson & Johnson) (ENSEMBLE study)6

September 21, 2020–January 22, 2021 8 countries worldwide Phase 3 Randomized (1:1), double-blind, placebo-controlled N = 39,321 Age ≥18 years Good/stable health Significant acute illness Temperature ≥38.0 C Allergy or anaphylaxis or other serious adverse reaction to vaccines or excipients Abnormal function of immune system Receipt or planning to receive intravenous immunoglobulin within previous 3 months or blood products in the 4 months before study Persons who were pregnant or breastfeeding Coexisting conditions that increased risk of severe COVID-19 Female: 45% White: 58% Black: 19% Hispanic/Latino: 6% Median age: 52 years (34% >60 years) Primary Efficacy Outcome: Moderate to severe-critical COVID-19 at least 14 days after single dose of vaccinee o Vaccine: 116 cases in 3116.6 person-years o Placebo: 348 cases in 3096.1 person-years o VE (95% CI): 66.9% (59.0–73.4%) Death o Vaccine: 3 (none COVID-19 related) o Placebo: 16 (5 COVID-19 related)

Local adverse events (V vs. P)f

Pain: 40% vs. 15% Redness: 6% vs. 10% Swelling: 4% vs. 3%

Systemic adverse events (V vs. P)

Fever: 7% vs. 0% Fatigue: 31% vs. 18% Headache: 32% vs. 20% Abbreviations: P, placebo; RT-PCR, reverse transcriptase-polymerase chain reaction; V, vaccine; VE, vaccine efficacy. a 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, combined with a respiratory specimen obtained during the symptomatic period (or within 4 days before or after symptoms) that was positive for SARS-CoV-2 by nucleic acid amplification-based testing, either at the central laboratory or at a local testing facility (using a protocol-defined acceptable test). b Calculated from EUA materials. c At least two of the following symptoms: fever (temperature ≥38℃), chills, myalgia, headache, sore throat, or new olfactory or taste disorder, or as occurring in those who had at least one respiratory sign or symptom and at least one nasopharyngeal swab, nasal swab, or saliva sample (or respiratory sample, if the participant was hospitalized) that was positive for SARS-CoV-2 by reverse transcriptase-polymerase chain reaction (RT-PCR) test. d Measured within 7 days of intramuscular injection. From VRBPAC data. e Mild COVID-19 defined as a SARS-CoV-2-positive RT-PCR or molecular test result from any available respiratory tract sample (eg, nasal swab sample, sputum sample, throat swab sample, saliva sample) or other sample AND One of the following symptoms: fever, sore throat, malaise, headache, myalgia, gastrointestinal symptoms, cough, chest congestion, runny nose, wheezing, skin rash, eye irritation or discharge, or chills, without shortness of breath or dyspnea. Moderate COVID defined as positive SARS-CoV-2 test as above AND any 1 new or worsening sign AND any new or worsening symptom. Severe/critical COVID-19 defined as positive SARS-CoV-2 test as above AND clinical signs at rest indicative of severe systemic illness, respiratory failure, evidence of shock, significant acute renal, hepatic, or neurologic dysfunction, admission to the ICU, or death. f Calculated from EUA materials.

Although some protection was conferred against COVID-19 after the first dose of active vaccine, optimal protection occurred 7 days after the second dose. Overall, data obtained from this analysis demonstrated 95.0% (90.3–97.6) vaccine efficacy (95% CI) against symptomatic COVID-19 in individuals 16 years and older over a median of 2 months meaning receipt of this vaccine reduced symptomatic COVID-19 when compared to no vaccine at all. Additionally, vaccine efficacy was similar regardless of age, gender, race, ethnicity, or coexisting conditions. The calculated vaccine efficacy and associated confidence interval met the FDA-pre-specified criteria for vaccine efficacy.

Pain at injection site was common after the first dose, while systemic reactogenicity was more common after the second dose in both the younger and older vaccine recipients. Mild-moderate local reactions tended to subside within 1–2 days. Fatigue, headache, and fever were the most common systemic reactions reported after the second dose of the vaccine. Fever and chills were typically observed within the first 1–2 days after vaccination and resolved shortly after. Younger vaccine recipients were more likely to take an antipyretic or pain medication (28% after first dose; 45% after second dose) than older recipients (20% after first dose; 38% after second dose) when compared to the placebo group (10%–14% after either dose).

3.2 mRNA-1273 COVID-19 vaccine (Moderna)

mRNA-1273 was evaluated in a two-dose vaccine series administered intramuscularly 28 days apart in 30,420 participants (15,210 in each group).5 The primary efficacy endpoint was COVID-19 (defined as RT-PCR positive SARS-CoV-2 with COVID-19 symptoms, Table 1) at least 14 days after the second injection in participants who were SARS-CoV-2 seronegative at baseline. Similar to BNT162b2, a cutoff date of November 25, 2020 occurred in order to provide at least 2 months of safety data after the second dose.

In this study, COVID-19 was more common in the placebo group compared with the mRNA-1273 group (Table 1). The vaccine efficacy (95% CI) was 94.1% (89.3%–96.8%) 14 days after administration of the second dose indicating reduced symptomatic laboratory-confirmed COVID-19 when compared to no vaccine against COVID-19. These findings met the FDA-pre-specified criteria for vaccine efficacy. A key difference that was noted in this analysis was the development of 30 cases of severe COVID-19 with 1 death in the placebo group compared with no cases of severe COVID-19 in participants receiving vaccination.

Injection-site reactions were generally mild and lasted 2.6 and 3.2 days after the first and second doses, respectively (Table 1). Delayed injection-site reactions (>8 days after injection) were rare (0.8% after first dose; 0.2% after second dose) and resolved within 5 days. Moderate-severe systemic reactogenicity (fatigue, myalgia, and headache) was commonly observed after the second dose of vaccine and began approximately 15 h after administration of the second dose. Like BNT162b2, younger participants categorized between the ages of 18 to <65 years were more likely to experience local and systemic reactogenicity.

3.3 Ad26.COV2.S COVID-19 vaccine (Johnson and Johnson/Janssen)

The third vaccine to be granted EUA in the United States is a single-dose recombinant adenovirus type 26 vector.6 In the pivotal study of Ad26.COV2.S, 19,630 participants received the vaccine and 19,691 received placebo. Primary endpoints in this analysis included vaccine efficacy against moderate to severe-critical COVID-19 at least 14 and 28 days after administration. Consistent with previous studies, to have enough safety data accrual, a data cutoff was instituted (January 22, 2021).

One hundred and sixteen cases of moderate to severe-critical COVID-19 occurred at least 14 days after vaccine administration compared with 348 in the placebo group. These data indicated that Ad26.COV2.S had a vaccine efficacy (95% CI) of 66.9% (59.0%–73.4%) against moderate to severe or critical COVID-19 compared with no vaccine against COVID-19. This point estimate and confidence interval met the FDA-pre-specified criteria for vaccine efficacy. Similar vaccine efficacy was seen 28 days after administration (Table 1). Differences between the vaccine and placebo groups in the development of COVID-19 became apparent 14 days after administration. The greatest protection the vaccine offered was against severe-critical COVID-19. Vaccine efficacy was reported to be 76.7% at least 14 days after administration and 85.4% at least 28 days post-administration.

Participants who received Ad26.COV2.S reported more local and systemic adverse events within 7 days of administration than those receiving the placebo (Table 1). Most local and systemic reactions appeared 1–2 days after administration and subsided in 1–2 days. Like the findings in the other vaccine trials, younger recipients experienced adverse events more frequently. Injection-site reactions occurred in almost half of the participants. Headache (39%), fatigue (38%), nausea (14%), and myalgia (33%) were the most common systemic reactions associated with the vaccine. Interestingly, venous thromboembolic events (VTE), seizures, and tinnitus were numerically higher in the vaccine group (VTE [11], seizure [4], and tinnitus [6]) compared with the placebo group (VTE [3], seizure [1], and tinnitus [0]). Three deaths occurred in the vaccine group, where none were COVID-related, compared with 16 in the placebo group, where 5 were COVID-related. Based on these findings, authors of this study concluded that a single dose of Ad26.COV2.S provided protection against asymptomatic SARS-CoV-2, as well as moderate to severe-critical COVID-19.6

In summary, three vaccines, BNT162b2, mRNA-1273, and Ad26.COV2.S, met the FDA pre-specified criteria for vaccine efficacy. Although there are some numerical differences between these vaccines, direct comparison between trials may not be possible due to differences in study design, SARS-CoV-2 strains, prevalence, and transmission dynamics. These items have been thoroughly reviewed elsewhere.7 The remainder of this review examines these and additional factors to consider when interpreting COVID-19 vaccine studies conducted outside of randomized controlled trials.

4 REAL-WORLD EFFECTIVENESS AND SAFETY OF COVID-19 VACCINES

Real-world data should also be considered to determine effectiveness of these vaccines outside of the highly controlled clinical trial environment. Several studies have examined how vaccination has affected documented SARS-CoV-2 infection, symptomatic SARS-CoV-2 infection (COVID-19), and asymptomatic SARS-CoV-2 infection (Table 2).8-13 A nationwide study of BNT162b2 demonstrated that effectiveness mirrored the efficacy observed in the clinical trials for preventing documented SARS-CoV-2 infection and COVID-19.8 BNT162b2 and mRNA-1273 also demonstrated effectiveness in high-risk individuals. In studies of healthcare workers, the proportion of those who became infected decreased with partial and complete vaccination status,9 and SARS-CoV-2 incidence was 0.17% among vaccinated persons.10 Collectively, these data suggest that in a real-world setting, these vaccines are highly efficacious at preventing SARS-CoV-2 infection.

TABLE 2. Real-world effectiveness of COVID-19 vaccines Vaccine Population Study design Key endpoints Key findings BNT162b28 Nationwide cohort (n = 596,618) Matched cohort within integrated healthcare organization, unstructured testing Vaccine Effectiveness (95% CI) for documented infection (VE-DI), symptomatic infection (VE-SI), and hospitalization (VE-H)a

VE-DI: 92% (88%–95%)

VE-SI: 94% (87%–98%)

VE-H: 92% (75%–100%)

BNT162b2 or mRNA-12739 Healthcare workers (n = 23,234) Cohort, unstructured testing SARS-CoV-2 incidence in unvaccinated (UV), partially vaccinated (PV), and fully vaccinated (FV)b

UV: 2.61%

PV:1.82%

FV: 0.05%

p < 0.01 for all pairwise comparisons

BNT162b2 or mRNA-127310 Healthcare workers (n = 4167) Cohort, weekly mandatory testing SARS-CoV-2 incidence 15 or more days after second dose of either vaccine 0.17% BNT162b2 or mRNA-127311 Patients undergoing preprocedural tests (n = 48,333) Cohort, mandatory testing Relative riskc (95% CI) of SARS-CoV-2 in vaccinated vs. unvaccinated any time after second dose 0.20 (0.09–0.44) BNT162b2 or mRNA-127312 Multistate, prospective cohort study of healthcare workers, first responders, and other essential and frontline workers (n = 3950) Active surveillance with weekly self-collected a midturbinate nasal swab Vaccine effectivenessd (95% CI) for combined COVID-19 and asymptomatic SARS-CoV-2 infection 91% (73%–97%) BNT162b213 Asymptomatic hospital workers (n = 5217) Cohort, minimum of once weekly testing Incidence rate ratio (95% CI) for any SARS-CoV-2 infection (AC), asymptomatic SARS-CoV-2 (AS), COVID-19 or known exposure cases (CK)e

AC: 0.21 (0.15–0.28)

AS: 0.28 (0.18–0.42)

CK: 0.16 (0.10–0.25)

a Vaccine effectiveness calculated as 1—risk ratio, using Kaplan-Meier Estimator, ≥7 days post second dose of BNT162b2. b Partially vaccinated individuals received one dose of BNT162b2 vaccine <7 days before index date or the second dose of mRNA-1273 vaccine less than 14 days before index date. Fully vaccinated persons were those who received the second dose of BNT162b2 vaccine at least 7 days before index date or the second dose of mRNA-1273 at least 14 days before the index date. c Mixed effects log-binomial regression adjusted for age, sex, race/ethnicity, patient residence relative to the hospital (local vs. non-local), healthcare system regions, and repeated screenings among patients. d Unadjusted vaccine effectiveness calculated as 100% × (1 – hazard ratio). Adjusted vaccine effectiveness (95% CI) with study site as covariate: 90% (68%–97%). e Confirmed cases per person-days of follow-up in vaccinated compared with unvaccinated groups using Kaplan-Meier estimator.

Another important consideration is the effect of vaccination on asymptomatic SARS-CoV-2 infection. Asymptomatic spread of SARS-CoV-2 may be a large contributor to the propagation of COVID-19 cases.14 Several observational studies have assessed the impact of vaccination on asymptomatic infection (Table 2). A retrospective cohort study of asymptomatic individuals screened during preprocedural testing found that vaccination decreased relative risk of SARS-CoV-2 any time after the second dose.11 Another study found that vaccination decreased the incidence rate ratios for SARS-CoV-2 infection, asymptomatic SARS-CoV-2, and COVID-19 (or any SARS-CoV-2 after known exposure) in asymptomatic hospital workers.13 In a different multistate, prospective cohort study of essential and frontline workers vaccine efficacy (95% CI) was estimated to be 91% (73%–97%) for reducing combined COVID-19 and asymptomatic SARS-CoV-2.12 Together, the results of these studies indicate that BNT162b2 and mRNA-1273 are likely effective at reducing asymptomatic SARS-CoV-2, a major contributor of COVID-19 spread. Of note, while not a real-world study, Ad26.COV2.S was found to prevent asymptomatic infection in clinical trials.6 It is also important to note that these studies were conducted prior to any meaningful effect of waning immunity or variants (see General Considerations for Immunity Post-Vaccination and Variants).

There are several important caveats to interpreting these data. In contrast to randomized controlled trials, these observational studies have many sources of heterogeneity. The first factor that clinicians should consider is the lack of uniform study design.7 These subtle variations can lead to misleading comparisons of vaccine products. For example, case-control studies that match COVID-19 cases with controls that have COVID-19 symptoms but negative SARS-CoV-2 tests (test-negative design) may be susceptible to misclassification bias based on the SARS-CoV-2 test used.15 Another consideration is measurement of vaccine effectiveness. Some of these studies quantify vaccine effectiveness as a function of 1—relative risk (RR) and others use hazard ratio (HR). While the RR and HR are both measures of association, they are not synonymous. Relative risks can differ from hazard ratios because the latter uses censorship to assess integrated probability of outcome over time, risks do not. Hence, risks may be more susceptible to bias from loss to follow-up as compared to hazards because risks do not inherently measure duration of subjects’ time within the cohort. Another consideration is differences in testing schemes used to ascertain SARS-CoV-2 infections. Some of these studies used frequent, regular, mandatory testing, while others relied on self-selected testing. The frequent, regular, mandatory testing used in some studies is likely to capture more cases, so comparison between studies may be difficult. Endpoint definitions (asymptomatic SARS-CoV-2, symptomatic SARS-CoV-2 [COVID-19], severe COVID-19, hospitalization, and death) also differed between studies. Additionally, differences between which tests were used, which symptoms were assessed, and regional hospitalization patterns can also influence the interpretation of these data.

Other considerations include the study population being evaluated.7 Populations with a high proportion of individuals in public-facing careers (eg, healthcare, food distribution) likely have a higher level of community exposure to SARS-CoV-2 than individuals who can shelter in place with minimal exposure. As a result, the incidence of SARS-CoV-2 estimates may be heterogeneous between those with public-facing exposure versus those without. Despite these limitations, it appears that the real-world effectiveness of these vaccines is like that which was observed in clinical trials.

Safety is another large concern among the public. In response, the US Centers for Disease Control and Prevention (CDC) established the V-safe adverse event monitoring system.16 V-safe is a voluntary program where participants self-enroll to receive text messages that connect them to web-based surveys at various time points post-vaccination. While this is an improvement from Vaccine Adverse Event Reporting System (VAERS), a spontaneous and voluntary reporting system, V-safe is limited by the quality of information obtained. Two major issues include: (i) being a voluntary system means that full denominator data a