In late December of 2019, cases of pneumonia caused by betacoronavirus SARS-CoV-2,
closely related to SARS-CoV, were reported in the city of Wuhan, China. SARS-CoV-2
has resulted in a worldwide pandemic that continues to surge throughout the United
States. Two vaccines for SARS-CoV-2 (the virus that causes COVID-19) are now available
under emergency use authorization (EUA). An EUA was issued for the Pfizer-BioNTech
COVID-19 vaccine on December 11, 2020, and another EUA was issued for the Moderna
COVID-19 vaccine on December 18, 2020. Development of a coronavirus vaccine is not
new. Vaccines against SARS-CoV were developed and tested in phase I trials in the
2000s, but development halted because of the disappearance of the virus.
1
Similarly, vaccines against Middle Eastern respiratory syndrome are under active development,
but not at an accelerated pace, because of extremely low prevalence of the virus.
The information gained from preclinical studies with SARS-CoV and Middle Eastern respiratory
syndrome laid the groundwork to identify the spike protein as a target for development
of a vaccine against SARS-CoV-2 at an early stage.
1
Current COVID-19 Vaccine Development
In response to the pandemic, vaccine development has moved expeditiously with more
than 200 COVID-19 vaccine candidates currently under development or in clinical trials.
2
These candidate vaccines are based on traditional approaches (inactivated or live
attenuated vaccines), methods that have resulted in newly licensed vaccines (recombinant
protein vaccine and vectored vaccines), and methods that have not resulted in a licensed
vaccine (RNA and DNA vaccines).
1
Vectored vaccines incorporate 1 or more viral genes into the genome of viral vectors.
These vectors are used to transport genetic material to host cells for transcription
and expression of the desired coronavirus antigen.
1
The Pfizer-BioNTech and Moderna vaccines use mRNA platforms. Preliminarily, these
vaccines are reported to be more than 90% efficacious at prevention of symptomatic
infections.
3
The vaccine antigen is coded by mRNA, which is protected by a lipoprotein coat. On
vaccine administration, cells pick up the mRNA and translate it into a protein (in
this case, the SARS-CoV-2 spike protein). The immune system then mounts a response
to that protein. Although no mRNA vaccines against other infectious agents are presently
available, mRNA vaccines have shown great promise, and in recent years many are in
development to treat cancer and other infectious disease, such as Zika virus and cytomegalovirus.
1
COVID-19 Vaccine Hesitancy
Widespread public acceptance and uptake of COVID-19 vaccines, in addition to concomitant
prevention strategies, will be imperative in containing the spread of disease. Unfortunately,
the general public’s confidence in a COVID-19 vaccine under the US government’s Operation
Warp Speed (OWS) initiative has been clouded in an environment of political polarization
and general mistrust of public health and governmental agencies. One survey found
that having a vaccine available under a Food and Drug Administration (FDA) EUA was
associated with a lower probability of willingness to get vaccinated, compared with
standard FDA licensure.
4
Vaccine hesitancy in adults is a complex issue and in general, there are few strategies
to ameliorate this. Increasing uptake of vaccines is important, especially in the
case of this pandemic, to achieve herd immunity and protect the general population.
The Centers for Disease Control and Prevention’s Vaccinate with Confidence campaign’s
strategic framework has been customized to increase support for COVID-19 vaccinations.
4
This campaign centers around the principles of reinforcing trust using transparent
communication about the process of licensing, and safety of, vaccines; empowering
health care providers to discuss vaccines with their patients by providing simple
talking points; and engaging communities and individuals to explore service delivery
strategies for vaccine distribution.
5
How Have COVID19 Vaccines Been Developed, How Will They Receive EUA/Approval
Multiple vaccines for COVID-19 are being developed and tested on an unprecedented
timeline. There are more than 200 vaccine candidates currently in development against
SARS-CoV-2, and there are several candidate vaccines in the United States that are
in active phase III clinical trials.
2
An overview of the typical timeline for vaccine development is illustrated in Figure 1
.
6
Vaccine development is a complex, expensive, and lengthy process, with the typical
timeline from preclinical studies to final licensure often ranging between 10 and
15 years.
7
The general public has voiced anxiety over the expedited timeline for vaccine development
under OWS, with concern that there is not strict adherence to the regulatory standards
for approval.
8
OWS, announced on May 15, 2020, is an initiative to control the COVID-19 pandemic
by advancing the development, manufacturing, and distribution of vaccines, therapeutics,
and diagnostics. OWS is a partnership of the Department of Health and Human Services,
the Department of Defense, and the private sector. These agencies are providing funding
and coordinated government support to accelerate vaccine development while still maintaining
standards for safety and efficacy. OWS has worked with vaccine developers to enable,
accelerate, and harmonize vaccine protocols of highly powered efficacy trials (Figure 1).
Rather than eliminating steps from the traditional vaccine development timeline, trial
phases are being combined and are proceeding simultaneously to expedite development.
6
Figure 1
CDC, Centers for Disease Control and Prevention; NEJM, New England Journal of Medicine;
NIH, National Institutes of Health.
Although vaccine development has been accelerated, no steps in the typical vaccine
development process have been skipped. Leadership of the FDA have emphasized that
candidate vaccines are being reviewed according to their rigorous established legal
and regulatory standards.
9
Vaccine efficacy and safety have been promising in several candidates to date. The
primary end point for all vaccines currently in phase III clinical trials is COVID-19
symptomatic disease, as illustrated in Table 1
.
Table 1
Vaccines in Parallel, Double-Blind, Placebo-Controlled, Efficacy Phase III Randomized
Clinical Trials in the United States
Vaccine type
Manufacturer
Trial participants
Randomization ratio/IM doses
Primary outcome
Secondary outcomes
mRNA
Moderna
30,000 participants, ages 18+
1:1/2
Incidence of COVID-19 casesParticipants with solicited local and systemic adverse
reactions
Immunogenicity of vaccine
mRNA
BioNTech-Pfizer
43,998 participants ages 12+
1:1/2
Incidence of COVID-19 casesIncidence of adverse events and serious adverse events
Immunogenicity of vaccine
Nonreplicating viral vector
AstraZeneca
40,051 participants ages 18+
2:1/2
Incidence of COVID-19 casesIncidence of adverse events, serious adverse events, medically
attended adverse events, adverse events of special interestSolicited local and systemic
adverse reactions
Immunogenicity of vaccine
Nonreplicating viral vector
Jansen
60,000 participants ages 18+
1:1/1
Incidence of moderate to severe/critical COVID-19 cases
Serologic conversionImmunogenicity of vaccine
The Advisory Committee on Immunization Practices (ACIP) has provided interim recommendations
for the currently available COVID-19 vaccines, as outlined in Table 2
.
10
These considerations are specific to the Pfizer and Moderna mRNA vaccines, which are
available for use under EUA. An EUA differs from vaccine licensure. An EUA allows
use of unapproved medical products to diagnose, treat, or prevent serious or life-threatening
diseases or conditions in response to a declared public health emergency for which
there are no adequate, approved, and available alternatives. The issuance of an EUA
requires a determination by the FDA that the vaccine’s benefits outweigh its risks
based on data from at least 1 well-designed phase III clinical trial that demonstrates
the vaccine’s safety and efficacy in a compelling manner. The FDA expects manufacturers
who receive an EUA to continue their studies to obtain comprehensive safety and effectiveness
information and pursue final licensure of their product.
11
,
12
An EUA still requires review of extensive safety and efficacy data from phases I and
II of vaccine studies, with an expectation that phase III data include a median follow-up
of at least 2 months for vaccine recipients. This 2-month timeframe was selected because
adverse events considered potentially linked to vaccination typically start within
6 weeks of vaccine receipt.
11
Vaccines made available with EUA will have met this safety requirement. Furthermore,
long-term safety data will continue to be collected for those in clinical trials and
those who receive the vaccine under an EUA with safety monitoring systems, such as
Vaccine Adverse Event Reporting System, the Vaccine Safety Datalink, and Clinical
Immunization Safety Assessment and safety review by the Institute of Medicine.
13
Table 2
Interim Recommendations for Use of mRNA COVID-19 Vaccines
Moderna
Pfizer
Authorized ages
≥18 y
≥16 y
Administration
Two doses administered intramuscularly: 100 μg, 0.5 mL; 28 d apart
Two doses administered intramuscularly: 30 μg, 0.3 mL each; 21 d apart
Interchangeability
COVID-19 vaccine are not interchangeable
Coadministration with other vaccines
Should be administered alone, with a minimum interval of 14 d before or after administration
with any other vaccine given the lack of data
Immunocompromised persons (eg, patients with inflammatory bowel disease or chronic
liver disease)
They should receive vaccinea
Vaccination of persons with SARS-CoV-2 infection or exposure
Offered to persons regardless of history of prior symptomatic or asymptomatic SARS-CoV-2
infectionPersons with known current SARS-CoV-2 infection should be deferredb
Vaccination of pregnant individualsc
Pregnant people who are part of a group recommended to receive the vaccine (eg, health
care personnel) may choose to be vaccinated; a conversation of the risks and benefits
of this vaccination with a health care provider is recommended, although not required
Vaccination of lactating individualsd
A lactating person may choose to be vaccinated
Precautions
History of severe allergic reaction to any other vaccine or injectable therapye
Contraindications
Severe allergic reaction to any component of the vaccinef
a
These populations should be counseled about the unknown vaccine safety profile and
effectiveness in immunocompromised populations, and the potential for reduced immune
responses.
b
Vaccination should be deferred until the person has recovered from acute illness (if
symptomatic) and criteria have been met to discontinue isolation.
c
Limited data on the safety of the vaccine in pregnant people. Routine pregnancy testing
is not required before receipt of the vaccine, and those who are trying to become
pregnant do not need to avoid pregnancy after vaccination. There were no safety concerns
with the Moderna vaccine demonstrated in rats in terms of female reproduction, development,
or postnatal development.
d
There are no data on the safety of the vaccine in lactating people. The vaccine is
not thought to be a risk to the breast-feeding infant.
e
No precautions necessary for dose with history of food, pet, insect venom, environmental,
latex, or other allergies not related to vaccines or injectable therapies.
f
Pfizer-BioNTech COVID-19 vaccine ingredients: 1,2-distearoyl-sn-glycero-3-phosphocholine,
2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, cholesterol, (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate),
potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium
phosphate dihydrate, and sucrose. Moderna COVID-19 ingredients: polyethylene glycol
2000 dimyristoyl, 1,2-distearoyl-sn-glycero-3-phosphocholine, cholesterol, SM-102
(proprietary to Moderna), tromethaminelycerol, tromethamine hydrochloride, acetic
acid, sodium acetate, and sucrose.
Role of the US Advisory Committee on Immunization Practice
The FDA has indicated that any decision about vaccine EUA or licensures will be discussed
by the ACIP.
9
The ACIP is a group that provides advice to the Centers for Disease Control and Prevention
Director and the Secretary of the Department of Health and Human Services. Because
of their standing as a federal advisory committee, they hold open meetings with public
involvement, and report their recommendations transparently. In addition to the 15
voting members, the committee has ex officio members and representation from liaison
organizations, such as the American Medical Association and the American Academy of
Pediatrics.
14
Although the ACIP generally holds meetings 3 times per year, during which they develop
the childhood and adult immunization schedules and make recommendations for vaccine
use in the United States, they have been meeting monthly to prepare recommendations
for COVID-19 vaccines.
14
The ACIP convened and recommended the Pfizer and Moderna vaccines before the issuance
of an EUA by the FDA.
COVID-19 Vaccine Allocation
With vaccines available, several considerations need to be taken to ensure fair and
equitable access to this limited resource. The ACIP has provided recommendations on
which groups should be prioritized for the earliest allocations of the vaccine. These
recommendations were centered around 4 ethical principles: (1) maximize benefits and
minimize harms, (2) promote justice, (3) mitigate health inequities, and (4) promote
transparency.
15
A phased allocation of vaccines is planned. On December 2, 2020, the ACIP voted and
stated that when a COVID-19 vaccine is authorized by the FDA and recommended by the
ACIP, vaccination in the initial phase of the COVID-19 vaccination program (Phase
1a) should be offered to health care personnel and residents of long-term care facilities.
This will be followed by those in phase 1b, which consists of frontline essential
workers and persons age 75 years and older. Phase 1c will include persons age 65–74
years and those age 16–64 with high-risk conditions. Finally, phase 2 will include
all other healthy adults.
Take Home Message
The COVID-19 vaccines that are first made available to health care personnel and residents
of long-term care facilities, followed by other individuals at high risk for complications
of COVID-19, have met rigorous efficacy and safety standards with no shortcuts taken
in their development. It is essential to actively address the spread of distrust and
misinformation surrounding vaccines for COVID-19. Clinicians must feel comfortable
educating patients that all of the appropriate steps are being taken to ensure that
the COVID-19 vaccine is safe and effective, to help dispel vaccine hesitancy among
patients.