Vaccines to prevent SARS-CoV-2 infection

Antigenic target — The major antigenic target for both SARS-CoV-1 and

MERS vaccines was the large surface spike protein [11-13]. An analogous
protein is also present in SARS-CoV-2; it binds to the angiotensin-converting
enzyme 2 (ACE2) receptor on host cells and induces membrane fusion (figure
2) [14]. Based on data from SARS-CoV-1 and MERS-CoV vaccine studies, as
well as observations that antibodies binding to the receptor-binding domain
(RBD) of the SARS-CoV-2 spike protein can prevent attachment to the host cell
and neutralize the virus, the spike protein became the predominant antigenic
target for COVID-19 vaccine development [15].

Immunologic basis for SARS-CoV-2 vaccination — Several observations

support the concept that vaccination has the potential to prevent SARS-CoV-2
infection. In nonhuman primate studies, experimental infection with wild-type
SARS-CoV-2 virus protected against subsequent reinfection, indicating that
infection can result in protective immunity [19,20]. Vaccination of primates also
protected against viral challenge; development of functional neutralizing
antibodies correlated with protection [21-23]. Epidemiologic studies in humans
have also suggested that neutralizing antibodies are associated with protection
from infection, as illustrated in an outbreak on a fishing vessel [24]. Thus,
vaccines that elicit a sufficient neutralizing response should be able to offer
protection against COVID-19.

The site of vaccine delivery may impact the character of the immune response
[15]. Natural respiratory infections elicit both mucosal and systemic immune
responses. Most vaccines, however, are administered intramuscularly (or
intradermally) and elicit primarily a systemic immune response, with less robust
protection in the upper respiratory mucosa than after natural infection. Some
vaccines can be administered intranasally, approximating natural infection, and
these may elicit a mucosal immune response, although they typically do not
induce as high of a systemic antibody response as inactivated vaccines do
[25,26]. Live attenuated COVID-19 vaccines administered to the respiratory
tract are undergoing preclinical studies.

Vaccine platforms — COVID-19 vaccines are being developed using several

different platforms (figure 3) [15]. Some of these are traditional approaches,
such as inactivated virus or live attenuated viruses, which have been used for
inactivated influenza vaccines and measles vaccine, respectively. Other
approaches employ newer platforms, such as recombinant proteins (used for
human papillomavirus vaccines) and vectors (used for Ebola vaccines). Some
platforms, such as RNA and DNA vaccines, have never been employed in a
licensed vaccine. General descriptions of the different platforms used for
COVID-19 vaccines are presented here.
●Inactivated vaccines – Inactivated vaccines are produced by growing
SARS-CoV-2 in cell culture then chemically inactivating the virus [27,28].
The inactivated virus is often combined with alum or another adjuvant in
the vaccine to stimulate an immune response. Inactivated vaccines are
typically administered intramuscularly. They require a biosafety level 3
facility for production. Immune responses to a SARS-CoV-2 inactivated
vaccine would target not only the spike protein but also other components
of the virus. Prototype inactivated COVID-19 vaccines are being developed
in China, India, and Kazakhstan; several are in late-stage clinical trials.

●Live attenuated vaccines – Live attenuated vaccines are produced by

developing genetically weakened versions of the wild-type virus; these
weakened viruses replicate in the recipient to generate an immune response
but do not cause disease [27,28]. Attenuation can be achieved by modifying
the virus genetically or by growing it in adverse conditions so that virulence
is lost but immunogenicity is maintained. A live attenuated COVID-19
vaccine would hopefully stimulate both humoral and cellular immunity to
multiple components of the whole attenuated virus. Another advantage of
live vaccines is that they can be administered intranasally, as with the live
attenuated influenza vaccine, which might induce mucosal immune
responses at the site of viral entry in the upper respiratory tract. However,
safety concerns with live attenuated vaccines include reversion to or
recombination with the wild-type virus. Several live attenuated COVID-19
vaccines are in pre-clinical development, but none have reached human
trials [2].
●Recombinant protein vaccines – Recombinant protein vaccines are
composed of viral proteins that have been expressed in one of various
systems, including insect and mammalian cells, yeast cells, and plants.
These vaccines are typically administered intramuscularly. They do not
require replication of the live virus, which facilitates production, although
production yields depend on the ability to express the spike protein, which
is variable. Recombinant COVID-19 vaccines in development include
recombinant spike protein vaccines, recombinant RBD vaccines, and virus-
like particle (VLP) vaccines [2]. A recombinant spike protein vaccine in
late-phase clinical trials is discussed elsewhere.
●Vector vaccines
•Replication-incompetent vector vaccines – Replication-incompetent
vector vaccines use a different vector virus that has been engineered to
not replicate in vivo and to express the viral protein that is the intended
immune target. Many replication-incompetent vector vaccine
candidates use adenovirus vectors, but other vectors include modified
 vaccinia Ankara (MVA), human parainfluenza virus, influenza virus,
adeno-associated virus (AAV), and Sendai virus [2]. One drawback to
vector vaccines is that pre-existing immunity to the vector can attenuate
immunogenicity of the vaccine [29]. This can be avoided by using viral
vectors that are uncommon in humans, vectors derived from animal
viruses, such as a chimpanzee adenovirus, or vectors that do not induce
self-immunity, such as AAV. Most SARS-CoV-2 replication-
incompetent vector vaccines in development are administered
intramuscularly and are engineered to express the spike protein, with a
resultant host immune response to that protein. Several are in late phase
clinical trials.

•Replication-competent vector vaccines – Replication-competent

vectors are derived from attenuated or vaccine strains of viruses. Using
replication-competent vectors often results in a more robust immune
response than with replication-incompetent vectors, since they replicate
within the vaccinated individual and trigger an innate immune
response. Among COVID-19 vaccine candidates, replication-competent
vectors have been engineered to express the spike protein in measles
vaccine strain vectors, influenza virus-based vectors, vesicular
stomatitis virus (VSV) [2], and Newcastle disease virus (NDV)
[2,30,31]. NDV-based vectors propagate to high titers in eggs and
could be produced using the global influenza vaccine production
pipeline; they could also be given intranasally to stimulate mucosal
immunity at the site of viral entry. Several replication-competent vector
vaccines are in early-phase clinical trials.
•Inactivated virus vector vaccines – Inactivated virus vectors are
engineered to express the target protein but have been inactivated and
are thus safer since they cannot replicate, even in the
immunocompromised host. Inactivated virus vector COVID-19
vaccines that display spike protein on the surface are still in the
preclinical stage of development.
●DNA vaccines – DNA vaccines consist of plasmid DNA that contain
mammalian expression promotors and the target gene, so that the target
protein is expressed in the vaccine recipient. Large quantities of stable
plasmid DNA can be generated in Escherichia coli, which is a major
production advantage. However, DNA vaccines are often of low
immunogenicity and need special delivery devices, such as electroporators,
which limit their use. Further, DNA vaccines must reach the nucleus to be
transcribed to messenger RNA (mRNA) so proteins can be generated to
stimulate an immune response. SARS-CoV-2 DNA vaccines in
development contain the spike protein gene as the target [22].
 ●RNA vaccines – RNA vaccines were the first vaccines for SARS-CoV-2
to be produced and represent an entirely new vaccine approach. Once
administered, the RNA is translated into the target protein, which is
intended to elicit an immune response. The mRNA remains in the cell
cytoplasm and does not enter into the nucleus; mRNA vaccines do not
interact with or integrate into the recipient's DNA. These vaccines are
produced completely in vitro, which facilitates production. However, since
the technology is new, the ability to produce large quantities of RNA
vaccines has not been previously tested, and some of the vaccines must be
maintained at very low temperatures, complicating storage. Some SARS-
CoV-2 RNA vaccines are now available.

IMMUNOGENICITY, EFFICACY, AND SAFETY OF SELECT

VACCINES The first human clinical trials of COVID-19 vaccines began

in March 2020, several phase III trials have been completed, and several more
are nearing completion. Select vaccine candidates that have completed, entered,
or are nearing entry into phase III trials are described here; some of these
vaccines are available for use in different countries. They represent different
vaccine approaches, including RNA vaccines, replication-incompetent vector
vaccines, recombinant protein vaccines, and inactivated vaccines; the general
features of these different platforms are described elsewhere. (See 'Vaccine
platforms' above.)
These vaccines have elicited neutralizing and cellular responses in nonhuman
primates without evidence of enhanced disease [4,5,21-23]. They have
demonstrated immunogenicity in early-phase human trials, most of which
compared receptor-binding antibody and neutralizing antibody titers to those
found in serum from patients convalescing from prior SARS-CoV-2 infection
(ranging from asymptomatic to severe infection) [15]. It is difficult to compare
the immunogenicity of the different vaccine candidates based on these studies,
in part because of the heterogeneity of the assays employed. None of the early
trials identified major safety concerns, but all vaccines elicited systemic adverse
effects (fever, chills, headache, fatigue, myalgia, joint pains) in a proportion of
participants, some of whom rated the effects severe enough to limit daily
activity.
Although results of phase III efficacy trials have been reported for several
COVID-19 vaccine candidates and indicate efficacy in preventing symptomatic
COVID-19, many uncertainties remain. These include vaccine effects on
microbiologically confirmed SARS-CoV-2 infection (both asymptomatic and
symptomatic, which could have implications for transmission) as well as the
durability of protective effect. (See 'Outstanding efficacy uncertainties' below.)
None of the vaccines have been studied against one another, and thus,
comparative efficacy is uncertain. Differences in the magnitudes of effect
reported from phase III trials might be related to factors other than
effectiveness, including differences in the trial populations and locations, timing
of the trials during the pandemic, and study design.

BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) — This mRNA vaccine is

delivered in a lipid nanoparticle to express a full-length spike protein. It is given
intramuscularly in two doses three weeks apart. BNT162b2 has been authorized
for use in several locations, including the United States, the United Kingdom
(UK), the European Union, and Canada [32,43-45]. Clinical use of the vaccine
is discussed elsewhere. (See 'Approach to vaccination' above.)
●Immunogenicity – In a phase I/II randomized, placebo-controlled,
observer-blind dose escalation study in healthy adults 18 to 85 years of age,
binding and neutralizing antibody responses were demonstrated that were
comparable to those in convalescent plasma from patients who had
asymptomatic or moderate SARS-CoV-2 infection [46]. Responses in
participants ≥65 years old were generally lower than in younger subjects,
but still comparable to titers in convalescent plasma. Plasma from trial
participants vaccinated with BNT162b2 appears to maintain neutralizing
activity against B.1.1.7, a viral variant that has emerged as the dominant
variant in the United Kingdom and has been identified in other countries
[47]. It also neutralizes virus containing key mutations found in B.1.351, a
viral variant that has emerged as the dominant variant in South Africa,
although neutralizing titers are lower (0.8 to 1.4 log lower) than those for
other circulating strains [48]. (See "Coronavirus disease 2019 (COVID-19):
Epidemiology, virology, and prevention", section on 'Notable variants'.)
●Efficacy – In a large placebo-controlled phase III trial, this vaccine had 95
percent efficacy (95% CI 90.3-97.6) in preventing symptomatic COVID-19
at or after day 7 following the second dose [49,50]. This effect was assessed
after an analysis of 170 confirmed COVID-19 cases (8 in the vaccine group
and 162 in the placebo group) among over 36,000 participants aged 16
years and older with a median of two months follow-up after vaccination.
Nine of the 10 severe cases that occurred during the study were in the
placebo group. Among adults ≥65 years who had other medical
comorbidities or obesity, vaccine efficacy was 91.7 percent (95% CI 44.2-
99.8). Among the entire trial population, the rate of COVID-19 in the
vaccine group started to decrease relative to the rate in the placebo group
approximately two weeks after the first dose, suggesting some efficacy of a
single dose (estimated vaccine efficacy of 52 percent, 95% CI, 29.5-68.4
 between the two doses). Similar findings were suggested by an unpublished
analysis of data from Israel following the roll-out of BNT162b2 [51].
Among over 350,000 individuals, the rate of SARS-CoV-2 infection (both
symptomatic and asymptomatic) was lower from days 13 to 24 compared
with ≤12 days following receipt of the first dose (0.27 versus 0.57 percent;
an estimated 51 percent reduction). However, the actual magnitude and
duration of protection from a single dose is unknown because most
participants in the trial and the cohort study received the second dose three
weeks after the first.
●Safety and side effects – Local and systemic adverse effects were dose
dependent and relatively common after the second dose; most were of mild
or moderate severity (ie, did not prevent daily activities). Among
participants younger than 55 years, fever occurred in 16 percent and severe
fatigue, headache, and chills, occurred in 4, 3, and 2 percent, respectively
[49]. Rates among older participants were slightly lower. Anaphylaxis
following vaccination has been reported at an approximate rate of 5 events
per one million doses [39]. Following the first 10 million doses of
BNT162b2 administered in the United States, 50 episodes were reported to
the CDC; this reflects a lower risk than had initially been estimated [52,53].
Of the anaphylaxis cases, 80 percent occurred in individuals with a history
of allergic reactions and 90 percent occurred within 30 minutes. Other
reported allergic reactions included pruritus, rash, scratchy sensations in the
throat, and mild respiratory symptoms [52]. Rare cases of Bell's palsy were
also noted in the phase III trial (four in vaccine and zero in placebo
recipients) [49]; however, the rate did not exceed background rates found in
the general population (15 to 30 cases per 100,000 people per year), and
post-vaccine monitoring has not identified an association between
vaccination and Bell’s palsy [39].
mRNA-1273 (Moderna COVID-19 vaccine) — This messenger RNA
(mRNA) vaccine was one of the first vaccines for SARS-CoV-2 to be produced;
it was developed and administered to humans within two months of publication
of the SARS-CoV-2 genomic sequence. The vaccine utilizes mRNA delivered
in a lipid nanoparticle to express a full-length spike protein. It is given
intramuscularly in two doses 28 days apart. mRNA-1273 has been authorized
for use in the United States and the European Union [33,54]. Clinical use of the
vaccine is discussed elsewhere. (See 'Approach to vaccination' above.)
●Immunogenicity – A phase I open-label trial demonstrated binding and
neutralizing antibody responses comparable to those seen in convalescent
plasma with vaccination in healthy individuals 18 to 55 years of age [55].
CD4 cell responses with a Th1 bias were also detected. Vaccination in
adults older than 55 years also elicited immune responses that were
comparable to those seen in the younger populations [56]. Binding and
neutralizing antibody responses declined slightly over three months in
participants from all age groups but remained elevated compared with
levels seen in convalescent plasma [57]. Based on preliminary, unpublished
data, plasma from trial participants vaccinated with mRNA-1273 appears to
maintain neutralizing activity against B.1.1.7, a viral variant that has
emerged as the dominant variant in the United Kingdom; it also neutralizes
B.1.351, a viral variant that has emerged as the dominant variant in South
Africa, but at up to sixfold lower titers than with wild-type virus [58]. The
clinical significance of this decrease in activity is unclear, although it seems
likely that mRNA-1273 vaccine-induced immunity will still be protective
against the B.1.351 variant. (See "Coronavirus disease 2019 (COVID-19):
Epidemiology, virology, and prevention", section on 'Notable variants'.)
●Efficacy – In a large placebo-controlled phase III results, mRNA-1273
had 94.1 percent vaccine efficacy (95% CI 89.3-96.8) in preventing
symptomatic COVID-19 at or after 14 days following the second dose [59].
This effect was assessed after an analysis of 196 confirmed COVID-19
cases (11 in the vaccine group and 185 in the placebo group) among nearly
30,000 study participants aged 18 years and older with a median follow-up
of two months after vaccination. Among adults ≥65 years of age, vaccine
efficacy was 86.4 percent (95% CI 61.4-95.5). Thirty cases were severe,
and all of these occurred in the placebo group. Among approximately 2000
participants who only received a single dose of vaccine or placebo, vaccine
efficacy following the dose was 80.2 percent (95% CI 55.2-92.5); however,
these individuals only had a median follow-up time of 28 days, so the
duration of protection from a single dose remains uncertain. A preliminary
analysis also suggested a reduction in asymptomatic infections between
dose 1 and 2 [60].
●Safety and side effects – Local and systemic adverse effects were dose
dependent and relatively common after the second dose; most were of mild
or moderate severity (ie, did not prevent daily activities or require pain
relievers) [61]. Among participants younger than 65 years, fever occurred
in 17 percent, and severe fatigue, headache, myalgias, and arthralgias
occurred in 10, 5, 10, and 6 percent, respectively. Adverse effects were less
frequent among older individuals; individuals with evidence of prior SARS-
CoV-2 infection also had lower rates of adverse effects than those without
prior infection. Anaphylaxis following vaccination has been reported at an
approximate rate of 2.8 events per one million doses [39,62]. Following the
first 7,581,429 doses of mRNA-1273 administered in the United States, 21
cases of anaphylaxis were reported to the CDC; 86 percent occurred among
individuals with pre-existing allergies, and 90 percent occurred within 30
minutes. There were rare cases of Bell's palsy that were considered
potentially related to vaccination (three in the vaccine and one in the
placebo group). However, the rate did not exceed the background rate in the
general population (15 to 30 cases per 100,000 people per year), and post-
 vaccine monitoring has not identified an association between vaccination
and Bell's palsy [39].
NVX-CoV2373 (Novavax) — This is a recombinant protein nanoparticle
vaccine composed of trimeric spike glycoproteins and a potent Matrix-M1
adjuvant. The vaccine is given intramuscularly in two doses 21 days apart. In a
phase I/II randomized, placebo-controlled trial of healthy individuals <60 years
old, the adjuvanted vaccine induced high binding and neutralizing responses,
comparable to those in convalescent plasma from patients who had been
hospitalized with COVID-19 [63]. CD4 cell responses with a Th1 bias were
also detected. Approximately 6 percent of participants experienced severe
systemic effects (mainly fatigue, headache, myalgias, and/or malaise) following
the second dose.
In a press release concerning a phase III efficacy trial, NVX-CoV2373 had 89.3
percent (95% CI 75.2-95.4) efficacy in preventing symptomatic COVID-19
starting at or after seven days following the second dose in seronegative
individuals [64]. This effect was assessed after interim analysis of 62 confirmed
COVID-19 cases (6 in the vaccine group and 56 in the placebo group) among
over 15,000 individuals aged 18 to 84 years. Only one of those cases was severe
and occurred in the placebo group. The vaccine appeared to be highly effective
against the variant B.1.1.7. However, in a smaller trial in South Africa, where
most COVID-19 cases were caused by the B.1.351 variant, vaccine efficacy
appeared lower, at 49.4 percent (95% CI 6.1-72.8). Serious adverse events
occurred at similar rates in the vaccine and placebo groups.
ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the
Serum Institute of India) — This vaccine is based on a replication-
incompetent chimpanzee adenovirus vector that expresses the spike protein. It is
given intramuscularly and is being evaluated as two doses 4 to 12 weeks apart.
The WHO recommends that the two doses be given 8 to 12 weeks apart [65].
ChAdOx1 nCoV-19/AZD1222 has been authorized for use in the European
Union and several other countries, including the United Kingdom and India.
Although there is some concern about vaccine efficacy against certain SARS-
CoV-2 variants, as discussed below, WHO recommends use of this vaccine
even if those variants are circulating in a country [65].
●Immunogenicity – In a single-blind, randomized controlled phase I/II
trial in healthy individuals 18 to 55 years old, in which most of the vaccine
recipients received a single dose and a small cohort received an additional
booster dose, neutralizing antibody titers 28 days after the last dose were
comparable to those detected in convalescent plasma [66]. The levels of
antibody titers achieved were higher following two doses; and subsequent
studies are evaluating the two-dose regimen. Cellular immune responses
were also detected. In a study that included older vaccine recipients (>70
years), the vaccine resulted in similar antibody responses after the second
dose as in younger adults [67].
●Efficacy – In a report of interim results from a multinational phase III
randomized trial, this vaccine had 70.4 percent efficacy (95% CI 54.8-80.6)
in preventing symptomatic COVID-19 at or after 14 days following the
second dose [68]. This effect was assessed after an analysis of 131
confirmed COVID-19 cases (30 in the vaccine group and 101 in the control
group) among over 11,000 participants with a median follow-up of two
months after vaccination. Ten participants were hospitalized for COVID-
19, including two who were categorized as having severe disease; all of
them were in the control group. A subgroup of participants inadvertently
received a lower vaccine dose for the first of the two vaccine doses, and the
overall vaccine efficacy in this subgroup differed from the rest. Vaccine
efficacy was 90.0 percent (95% CI 67.4-97.0) among the 2741 participants
who received the lower dose and 62.1 percent (95% CI 41-75.7) among
those who received full-dose vaccine. Reasons for this difference are
uncertain, although the overlapping confidence intervals indicate that the
difference is not statistically significant. Differences in the control
administered (meningococcal vaccine for both doses at some study sites
versus meningococcal vaccine for one dose with saline for another dose at
other sites) and in the interval between administration of the two vaccine
doses further contribute to uncertainty about the findings.
In a subsequent unpublished analysis of this trial, vaccine efficacy for
symptomatic COVID-19 was 76 percent from 21 days after receipt of the
first dose until receipt of the second dose or day 90, whichever came first,
suggesting protection with a single dose [69]. Additionally, receipt of the
second dose at 12 weeks or later was associated with higher vaccine
efficacy than receipt at <6 weeks (81 versus 55 percent). These findings
lend support to extending the time interval for the second dose to 12 weeks.
According to another unpublished report, vaccine efficacy against B.1.1.7, a
viral variant that has emerged as the dominant variant in the United
Kingdom and has been identified in other countries, compared with other
variants was not statistically different (75 versus 84 percent), despite
induction of lower neutralizing activity against the B.1.1.7 variant [70].
However, according to preliminary, unpublished results of a phase I/II trial
in South Africa, ChAdOx1 nCoV-19/AZD1222 did not reduce the rate of
mild to moderate COVID-19 (at least one symptom but no tachypnea,
hypoxia, or organ failure) over a time frame when B.1.351 was the
dominant variant circulating [71,72]. Because the trial was small and the
number of cases was low, the estimate of vaccine efficacy had very wide
confidence intervals (21.9 percent, 95% CI -49.9 to 59.8). Impact on severe
disease, which was rare in the young, healthy trial population, could not be
assessed.
●Safety and side effects – In earlier-phase trials, fatigue, headache, and
fever were relatively common after vaccine receipt and were severe in up to
 8 percent of recipients [66]. In the phase III trial, there were two cases of
transverse myelitis in ChAdOx1 nCoV-19 vaccine recipients [68]. One was
thought to be possibly related to vaccination and was described as an
idiopathic, short-segment spinal cord demyelination; the other was in a
participant with previously unrecognized multiple sclerosis and thought to
be unrelated to the vaccine.
Ad26.COV2.S (Janssen) — This vaccine is based on a replication-incompetent
adenovirus 26 vector that expresses a stabilized spike protein. It is given
intramuscularly and is being evaluated as a single dose or two doses 56 days
apart. A phase I/II randomized, double-blind, placebo controlled trial described
high rates of neutralizing and binding antibodies after a single vaccine dose in
healthy individuals 18 to 85 years old; these responses overlapped with but were
slightly lower than those in convalescent plasma [73]. A second vaccine dose
was evaluated in a subset of participants, and this resulted in an increase in
neutralizing titers. CD4 cell responses with a Th1 bias were also detected after
the first dose. Local injection site and systemic adverse effects (fatigue,
headache, myalgia) were common; the rate of grade 3 systemic adverse effects
ranged from 9 to 20 percent, depending on the vaccine dose, among participants
younger than 65 years, but was less than 2 percent among older participants.
Adenovirus 26 vectors are used in an Ebola vaccine that is licensed in Europe
and in RSV, HIV, and Zika vaccine candidates. Baseline seroprevalence to
adenovirus 26 is low in North America and Europe; it is moderately high in sub-
Saharan Africa and Southeast Asia, although most seropositive individuals have
low neutralizing titers [74]. Nonhuman primate studies suggest that these low
titers do not suppress responses to adenovirus 26 vector vaccines.
In a press release report concerning a phase III efficacy trial that included
over 40,000 participants, Ad26.COV2.S, given as a single dose, had 66
percent efficacy in preventing moderate to severe COVID-19 (which
included patients with pneumonia, dyspnea, tachypnea, or at least two
systemic symptoms of COVID-19) starting at or after 14 days following
vaccination [75]. Efficacy against severe disease specifically was higher at
85 percent. Reported overall efficacy varied by region: 72 percent in the
United States, 66 percent in Latin America, and 57 percent in South Africa,
where most infections were caused by the variant B.1.351. Additional
details on the number of cases that occurred in each group were not
provided. Fever occurred following vaccination in 9 percent; overall,
serious adverse events were less frequent in the vaccine group than in the
placebo group.
Other vaccines
●Ad5-based COVID-19 vaccine (CanSino Biologics) – This vaccine is
based on a replication-incompetent adenovirus 5 vector that expresses the
spike protein. It is given as a single intramuscular dose. In early clinical
trials, it was immunogenic in healthy adults at 28 days with only mild to
moderate local and systemic reactions [76]. However, both pre-existing
immunity to adenovirus 5 and older age were associated with lower titers of
binding and neutralizing antibodies following vaccination; this may limit its
utility in locations where pre-existing immunity is prevalent. The vaccine
has been licensed in China for limited use by the military [77]. Prior studies
of adenovirus 5 vector HIV vaccine candidates identified an increased risk
of HIV acquisition among male vaccine recipients who were uncircumcised
and seropositive for adenovirus 5 at baseline [78]. It is uncertain whether
these observations are relevant for adenovirus 5 COVID-19 vaccines.
●Gam-COVID-Vac/Sputnik V (Gamaleya Institute) – This is a vaccine
developed in Russia that uses two replication-incompetent adenovirus
vectors that express a full-length spike glycoprotein. The vaccine is given
intramuscularly as an initial adenovirus 26 vector dose followed by an
adenovirus 5 vector boosting dose 21 days later. This vaccine is available in
Russia and several other countries, including Mexico.
In an open-label, nonrandomized phase I/II trial, SARS-CoV-2 humoral and
cellular immune responses were detected in the participants [79].
According to interim analysis of a phase III trial that included over 20,000
participants without serologic evidence of prior SARS-CoV-2 infection,
this vaccine had 91.6 percent (95% CI 85.6-95.2) efficacy in preventing
symptomatic COVID-19 starting at 21 days following the first dose (at the
time of the second dose) [79]. This effect was assessed after 78 cases of
COVID-19 (16 of 14,964 participants who received vaccine and 62 of 4902
participants who received placebo). All 20 cases of severe COVID-19 that
occurred 21 days after the first dose were in the placebo group. Median
follow-up time was 48 days after the first dose. Local and systemic, flu-like
reactions were more common in the vaccine group, at rates of 15 and 5
percent, respectively. No serious adverse events were deemed related to
vaccine.
●BBIBP-CorV (Sinopharm) – This is an inactivated vaccine based on a
SARS-CoV-2 isolate from a patient in China; it has an aluminum hydroxide
adjuvant. The vaccine is given intramuscularly in two doses 28 days apart.
In phase I/II placebo-controlled randomized trials of healthy individuals 18
to 80 years old, all recipients of two vaccine doses developed neutralizing
and binding antibodies; no severe reactions were reported [80,81]. This
vaccine is available in China and some other countries, including the United
Arab Emirates, based on interim data from a phase III efficacy data from
trial in that country [82].
●CoronaVac (Sinovac) – This inactivated COVID-19 vaccine was
developed in China; it has an aluminum hydroxide adjuvant. The vaccine is
given intramuscularly in two doses 28 days apart. In phase I/II randomized,
placebo-controlled trials, the vaccine appeared safe and immunogenic in
healthy individuals aged 18 to 59 years [83] as well as those 60 years or
 older [84]. This vaccine is available in China and some other countries,
including Brazil.

VACCINES IN INDIA

COVAXIN
COVAXINTM, India's indigenous COVID-19 vaccine Bharat Biotech is developed in
collaboration with the Indian Council of Medical Research (ICMR) - National Institute of
Virology (NIV). This indigenous, inactivated vaccine is developed and manufactured in
Bharat Biotech's BSL-3 (Bio-Safety Level 3) high containment facility.

The vaccine received approval from Drug Controller General of India (DCGI) for Phase I
& II Human Clinical Trials and an Adaptive, Seamless Phase I, Followed by Phase II
Randomized, Double blind, Multicentre Study to Evaluate the Safety, Reactogenicity,
Tolerability and Immunogenicity of the Whole-Virion Inactivated SARS-CoV-2 Vaccine
(BBV152).

Covishield
The Serum Institute of India (SII) and Indian Council of Medical Research are jointly
conducting a Phase II/III, Observer-Blind, Randomized, Controlled Study to Determine
the Safety and Immunogenicity of Covishield (COVID-19 Vaccine).

Of the two vaccines approved, Covishield is the better known. It’s a version of the
Oxford University-AstraZeneca vaccine that was found to have an average efficacy
of 70.4% in a peer reviewed study.

Both vaccines require two doses and work by priming the immune system with a
SARS-CoV-2 spike protein. Covishield uses a weakened version of adenovirus,
while Covaxin uses an inactivated SARS-CoV-2 virus extracted from an
asymptomatic patient.

ZyCoV-D
Zydus Cadila, focused on discovering and developing NCEs, Novel Biologicals,
Biosimilars and Vaccines, announced that its plasmid DNA vaccine to prevent COVID-
19, ZyCoV-D. Safety in Phase I clinical trial of ZyCoV-D in healthy subjects established
as endorsed by the independent Data Safety Monitoring Board (DSMB). Zydus
commenced Phase II trial.

Sputinik
Dr Reddys Laboratories Limited and Sputnik LLC are jointly conducting Multi-centre,
phase II/III adaptive clinical trial to assess safety and immunogenicity of Gam-COVID-
Vac combined vector vaccine.

Biological E’s novel Covid-19 vaccine

Biological E. Limited is conducting a prospective open label randomised Phase-I
seamlessly followed by Phase-II study to assess the safety, reactogenicity and
immunogenicity of Biological E’s novel Covid-19 vaccine containing Receptor Binding
Domain of SARS-CoV-2 for protection against Covid-19 disease when administered
intramuscularly in a two dose schedule (0, 28D) to healthy volunteers

APPROACH TO VACCINATION

United States
Indications — In the United States, the COVID-19 mRNA vaccines BNT162b2
(Pfizer-BioNTech COVID-19 vaccine) and mRNA-1273 (Moderna COVID-19
vaccine) have been granted emergency use authorization (EUA) for prevention of
COVID-19 [32,33]. We recommend vaccination with one of these vaccines in
individuals who are eligible for vaccination according to local allocation priorities.
●BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) is indicated for individuals
aged 16 years or older.
●mRNA-1273 (Moderna COVID-19 vaccine) is indicated for individuals aged 18
years or older.
As initial vaccine supplies are limited, the Advisory Committee on Immunization
Practices (ACIP) has recommended that these be allocated to health care
personnel and long-term care facility residents followed by adults 75 years or
older and frontline essential workers (table 1) [34,35] (see 'Allocation
priorities' below). Individual states have the ultimate responsibility for
determining vaccine eligibility then distributing and administering vaccine to
eligible populations, and allocation priorities differ by state. Clinicians should
refer to their local public health department for more detailed information.

The choice between these mRNA vaccines is based on availability. They have not
been compared directly, but they are similar in composition and, in their respective
phase III trials, showed similar efficacy and safety profiles. The differences in age
ranges included in the indications reflect the different age ranges included in the
phase III trials.

Details on the efficacy and safety of BNT162b2 and mRNA-1273 are discussed
elsewhere. (See 'Immunogenicity, efficacy, and safety of select vaccines' below.)
Dose and administration
●BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) is administered in two
intramuscular doses of 0.3 mL each, given three weeks apart.
Each vial of BNT162b2 contains at least five doses after dilution. With low dead-
space syringes, the volume in each vial may be sufficient to supply six full
doses; in such cases, all six doses can be administered [36]. However, any
residual volume less than a full dose (ie, <0.3 mL) should be discarded and
should not be pooled with residuals from other vials.
●mRNA-1273 (Moderna COVID-19 vaccine) is administered in two intramuscular
doses of 0.5 mL each, given one month apart.
In adults and adolescents, intramuscular vaccines are typically injected into the
deltoid. Proper injection technique to reduce the risk of shoulder injury involves
injection at a 90° angle into the central, thickest part of the deltoid (figure 4).
(See "Standard immunizations for nonpregnant adults", section on 'Technique'.)
The second dose of either mRNA vaccine should be given as close to the
recommended interval as possible [37]. If necessary, the second dose can be
scheduled for up to six weeks after the first dose. If the second dose is not given
within this time frame, it should be given as soon as feasible; the United States
Centers for Disease Control and Prevention (CDC) notes that the series does not
need to be repeated in such situations, although the efficacy of administering
vaccines beyond the recommended time frame is uncertain.
Each vaccine series should be completed with the same vaccine initially used [37];
there are no data to support the efficacy and safety of using one of the vaccines for
the first dose and another for the second. If extenuating circumstances result in
needing to complete the series with a different mRNA vaccine, the CDC
recommends that the second dose should be given at least 28 days after the first.

Other non-COVID-19 vaccines should not be administered within 14 days of COVID-

19 vaccine administration; there are no data regarding safety and efficacy when
COVID-19 vaccines are coadministered with other vaccines. Given the uncertainty,
however, a shorter interval between mRNA COVID-19 vaccines and other vaccines
is reasonable when timely administration of another vaccine is important (eg, tetanus
vaccination during wound management) or if it would avoid unnecessary delays in
COVID-19 vaccination.

There is no role for post-vaccination testing for COVID-19 unless clinically indicated.
Individuals may have local and systemic reactions (eg, fever, chills, fatigue,
headache) in the first one to two days after vaccination. However, respiratory
symptoms or systemic symptoms that occur after the first couple days following
vaccination could be indicative of COVID-19 and warrant testing. (See "Coronavirus
disease 2019 (COVID-19): Diagnosis", section on 'Initial testing and specimen
collection'.)
Additional details on administration can be found on the CDC website.
Special populations
History of SARS-CoV-2 infection — Individuals with a history of SARS-CoV-2
infection should still receive one of these vaccines, if indicated; pre-vaccination
serologic screening is not recommended [37]. If SARS-CoV-2 infection is diagnosed
following the first vaccine dose, the second dose should still be given.
Individuals with recent, documented SARS-CoV-2 infection should have recovered
from acute infection (if symptomatic) and met criteria for discontinuation of isolation
precautions before receiving either vaccine dose. It is also reasonable for such
individuals to delay vaccine receipt to allow others to receive vaccine sooner, as the
risk of reinfection appears extremely low in the first few months after infection. The
CDC also suggests that individuals who received monoclonal or convalescent
plasma therapy for COVID-19 should delay vaccination for at least 90 days from the
time of receipt [37]. This delay also applies to receipt of the second vaccine dose if
antibody-based COVID-19 therapy was administered after the initial vaccine dose.
Pregnant individuals — Safety of these vaccines has not yet been established in
children or pregnant individuals. However, pregnancy is not a contraindication to
vaccine receipt. The decision to vaccinate individuals 16 years and older who are
pregnant or breastfeeding should be made on a case-by-case basis, taking into
account the individual's preferences, risk of COVID-19, and the unknown fetal effects
of the vaccines. (See "Coronavirus disease 2019 (COVID-19): Pregnancy issues and
antenatal care", section on 'Vaccines' and 'Addressing special populations' below.)
Immunocompromised individuals — Eligible individuals with an
immunocompromising condition can also receive COVID-19 mRNA vaccines [37].
Although the immunogenicity and efficacy of the vaccines are uncertain in these
populations, the potential for severe COVID-19 in this population likely outweighs the
uncertainties.
Patient counseling — Vaccine recipients should be advised that side effects are
common and include local and systemic reactions, including pain at the injection site,
ipsilateral axillary lymph node enlargement, fever, fatigue, and headache. Although
analgesics or antipyretics can be taken if these reactions develop, pre-emptive use
of such agents is not recommended because of the uncertain impact on the host
response to vaccination [37].
In addition to standard counseling around vaccine information, vaccine providers are
required to inform potential recipients that each COVID-19 mRNA vaccine is
available under EUA and is not a licensed vaccine. (See 'Licensing a
vaccine' below.)
SARS-CoV-2 infection might still occur despite vaccination, and the duration of
protection is uncertain; vaccine recipients should be reminded to continue other
personal preventive measures to reduce SARS-CoV-2 transmission, such as
masking and physical distancing. However, the CDC allows waiving post-exposure
quarantine requirements for asymptomatic individuals who have completed a full
vaccination series at least two weeks before but no more than three months prior to
the exposure [37]. These interim recommendations limit the quarantine exemption to
the three months following vaccination because the duration of vaccine-induced
immunity is uncertain. (See "Coronavirus disease 2019 (COVID-19): Epidemiology,
virology, and prevention", section on 'Prevention' and "Coronavirus disease 2019
(COVID-19): Epidemiology, virology, and prevention", section on 'Post-exposure
management'.)
Contraindications and precautions (including allergies) — BNT162b2 (Pfizer-
BioNTech COVID-19 vaccine) and mRNA-1273 (Moderna COVID-19 vaccine) are
each contraindicated in [37]:
 ●Individuals with a severe allergic reaction, such as anaphylaxis, after a
previous dose of an mRNA COVID-19 vaccine or to any of its components
(including polyethylene glycol).
●Individuals with an immediate allergic reaction of any severity (including hives)
to a previous dose of an mRNA COVID-19 vaccine, to any of its components, to
polysorbate (with which there can be cross-reactive hypersensitivity to
polyethylene glycol). Such individuals should not receive an mRNA COVID-19
vaccine unless they have been evaluated by an allergy expert who determines
that it can be given safely.
Components of the mRNA COVID-19 vaccines are listed on the CDC website.
The ACIP lists history of severe allergic reaction to any other vaccine or injectable
therapy (that was not known [diagnosed] to be due to any of the components of an
mRNA COVID-19 vaccine or polysorbate) as a precaution, but not contraindication,
to vaccination [37].
All individuals should be monitored for immediate vaccine reactions following receipt.
Among those who do not have contraindications to vaccination, individuals who have
a history of anaphylaxis due to any cause or a history of immediate allergic reaction
of any severity to a vaccine or injectable therapy should be monitored for 30 minutes;
all others should be monitored for 15 minutes. Vaccines should be administered in
settings where immediate allergic reactions, should they occur, can be appropriately
managed. Recognition and management of anaphylaxis are discussed in detail
elsewhere (table 2). (See "Anaphylaxis: Acute diagnosis" and "Anaphylaxis:
Emergency treatment".)
Anaphylaxis has been reported following administration of both authorized mRNA
COVID-19 vaccines [38]. Following the first several million doses of mRNA COVID-
19 vaccines administered in the United States, anaphylaxis was reported at
approximate rates of 5 and 2.8 events per million doses for the BNT162b2 and
mRNA-1273 vaccines, respectively [39,40]. The vast majority of these events
occurred in individuals with a history of allergic reactions and occurred within 30
minutes. The mechanism for the anaphylaxis is under investigation and has not been
determined. Some suggest that it is IgE mediated, with polyethylene glycol as the
inciting antigen. However, other complement-mediated mechanisms have been
suggested in individuals without a previous history of allergy. Evaluation of patients
with possible anaphylaxis following COVID-19 vaccination is discussed elsewhere.
(See "Allergic reactions to vaccines", section on 'Possible anaphylaxis'.)
Late local reactions characterized by a well-demarcated area of erythema appearing
at the injection site approximately a week after vaccination have been reported. The
mechanism of these reactions is unknown, though some allergy experts suggest that
they are unlikely to be delayed type hypersensitivity reactions and recommend that
individuals who experience this reaction after the initial dose proceed with the
second dose as scheduled. (See "Allergic reactions to vaccines", section on 'Late
local reactions'.)
Facial swelling in areas previously injected with cosmetic dermal fillers has also been
rarely reported following vaccination. Dermal fillers are not a contraindication to
COVID-19 mRNA vaccination, and no specific precautions are recommended [37].
However, it is reasonable to advise individuals with dermal fillers of the possibility of
post-vaccination swelling. This is discussed elsewhere. (See "Coronavirus disease
2019 (COVID-19): Cutaneous manifestations and issues related to dermatologic
care", section on 'Soft tissue fillers'.)
Anticoagulation is not a contraindication to vaccination; excess bleeding is unlikely
with intramuscular vaccines in patients taking anticoagulants [41]. Such patients can
be instructed to hold pressure over the injection site to reduce the risk of hematoma.
(See "Standard immunizations for nonpregnant adults", section on 'Patients on
anticoagulation'.)
Reporting of adverse events — To facilitate ongoing safety evaluation, vaccine
providers are responsible for reporting vaccine administration errors, serious adverse
events associated with vaccination, cases of multisystem inflammatory syndrome
(MIS), and cases of COVID-19 that result in hospitalization or death through the
Vaccine Adverse Event Reporting System (VAERS). (See 'Ongoing safety
assessment' below.)
Details on the efficacy and safety of BNT162b2 and mRNA-1273 are discussed
elsewhere. (See 'Immunogenicity, efficacy, and safety of select vaccines' below.)
Other countries — Various vaccines are becoming available in different countries.
As examples, BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) has been authorized
for use in the United Kingdom (UK), the European Union, and Canada; mRNA-1273
(Moderna COVID-19 vaccine) has been authorized for use in the European Union;
ChAdOx1 nCoV-19/AZD1222 (University of Oxford/Astra Zeneca COVID-19 vaccine)
has been authorized for use in the European Union and several other countries,
including the United Kingdom and India; a different adenovirus vector vaccine
developed in Russia and several vaccines developed in China are available in
several countries. These have different dosing schedules and are in various stages
of evaluation, which are discussed elsewhere. (See 'Immunogenicity, efficacy, and
safety of select vaccines' below.)
Different countries may also have specific allocation priorities for distributing the
initial vaccine supplies. As an example, the Joint Committee on Vaccination and
Immunisation in the United Kingdom recommends prioritizing a first vaccine dose for
all eligible individuals prior to securing a second vaccine dose for recipients [42].
However, both mRNA vaccines were studied with two-dose schedules, and the
efficacy estimates from those schedules are difficult, if not impossible, to extrapolate
to a single-dose schedule. Clinicians should refer to local guidelines for vaccine
recommendations in their location.