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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has given rise to the urgent need for vaccines and therapeutic interventions to address the spread of the SARS-CoV-2 virus. SARS-CoV-2 vaccines in development, and those being distributed currently, have been designed to induce neutralizing antibodies using the spike protein of the virus as an immunogen. However, the immunological correlates of protection against the virus remain unknown. This raises questions about the efficacy of current vaccination strategies. In addition, safety profiles of several vaccines seem inadequate or have not yet been evaluated under controlled experimentation. Here, evidence from the literature regarding the efforts already made to identify the immunological correlates of protection against SARS-CoV-2 infection are summarized. Furthermore, key biological features of most of the advanced vaccines and considerations regarding their safety and expected efficacy are highlighted.
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Cytokine and Growth Factor Reviews xxx (xxxx) xxx
Please cite this article as: Maurizio Federico, Cytokine and Growth Factor Reviews, https://doi.org/10.1016/j.cytogfr.2021.03.001
Available online 6 March 2021
1359-6101/© 2021 Elsevier Ltd. All rights reserved.
The conundrum of current anti-SARS-CoV-2 vaccines
Maurizio Federico
National Center for Global Health, Istituto Superiore di Sanit`
a, Viale Regina Elena, 299, 00161, Rome, Italy
ARTICLE INFO
Keywords
SARS-CoV-2
Vaccine
Humoral immunity
Adenoviral vector
CD8
+
T-cell immunity
ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has given rise to the urgent need
for vaccines and therapeutic interventions to address the spread of the SARS-CoV-2 virus. SARS-CoV-2 vaccines
in development, and those being distributed currently, have been designed to induce neutralizing antibodies
using the spike protein of the virus as an immunogen. However, the immunological correlates of protection
against the virus remain unknown. This raises questions about the efcacy of current vaccination strategies. In
addition, safety proles of several vaccines seem inadequate or have not yet been evaluated under controlled
experimentation. Here, evidence from the literature regarding the efforts already made to identify the immu-
nological correlates of protection against SARS-CoV-2 infection are summarized. Furthermore, key biological
features of most of the advanced vaccines and considerations regarding their safety and expected efcacy are
highlighted.
1. Introduction
By the end of January 2021, severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) had infected more than 100 million people,
causing approximately 2.2 million deaths [1]. Given the nature and
severity of coronavirus disease (COVID-19), there is a need to ght the
viral spread through behavioral changes and social and medical in-
terventions. Among the latter, widespread efforts have been made to
produce vaccines for large-scale administration. All current vaccine
strategies have been developed to generate anti-spike protein (S)
neutralizing antibodies (Abs). This strategy has been pursued through
different technologies via the delivery of messenger RNA (mRNA),
adenoviral vectors, recombinant proteins, and inactivated viral
particles.
The urgency in tackling the pandemic strongly reduced the time
allocated to the three phases typically needed to achieve vaccine
licensure. However, unproven technologies have been proposed and
pursued to produce vaccines that are currently being distributed.
Applied on a global scale, these new strategies could achieve important
advancements in vaccine technology. However, in some cases, safety
concerns need to be revisited.
Furthermore, two additional aspects must be considered in the
overall evaluation of vaccines: efcacy and duration of immune
response. The immunological correlates of protection against SARS-
CoV-2 infection are still unknown. On the other hand, the restricted
observation times did not allow a reliable evaluation of the duration of
immune response induced by the current anti-SARS-CoV-2 vaccines.
Here, useful data are summarized from the literature to clarify the
course of humoral immunity in SARS-CoV-2-related pathogenesis in
humans. On this basis, the expected efcacy and the duration of immune
response of diverse vaccines are evaluated. In addition, possible issues
concerning the safety proles of the diverse vaccines are analyzed.
1.1. What is the immunological correlate of protection against SARS-CoV-
2 infection?
Most commonly, the term correlate of protectionrefers to a labo-
ratory parameter associated with protection from a clinical disease [2].
When this concept is applied to the immune response against
SARS-CoV-2, there are several uncertainties. For instance, data from a
detailed immunological study on hundreds of infected patients,
extended for up to 8 months after symptoms onset, did not provide
denitive conclusions about the mechanisms of protective immunity
[3]. On this basis, it has been proposed that a coordinated action of
CD4
+
T cells, CD8
+
T cells, and neutralizing Abs is necessary to control
SARS-CoV-2 infection [3,4]. Results from a study on rhesus macaques
Abbreviations: Ab, antibody; ACE-2, angiotensin-converting enzyme 2; ADE, antibody-dependent enhancement; COVID-19, coronavirus disease 2019; IgG,
immunoglobulin G; M, membrane protein; MHC, major histocompatibility complex; mRNA, messenger RNA; N, nucleocapsid protein; PEG, polyethylene glycol; PSO,
post symptoms onset; RBD, receptor-binding domain; S, spike protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
E-mail address: maurizio.federico@iss.it.
Contents lists available at ScienceDirect
Cytokine and Growth Factor Reviews
journal homepage: www.elsevier.com/locate/cytogfr
https://doi.org/10.1016/j.cytogfr.2021.03.001
Received 12 February 2021; Received in revised form 3 March 2021; Accepted 4 March 2021
Cytokine and Growth Factor Reviews xxx (xxxx) xxx
2
indicated that adequate levels of anti-SARS-CoV-2 immunoglobulin G
(IgG) can protect against infection and that cellular immunity contrib-
utes to protection in the case of subprotective Ab titers [5].
With regard to the virus-induced humoral response in humans, spe-
cic Ab responses were found to be elevated in severely ill patients, but
remained moderate-to-low or even undetectable in asymptomatic sub-
jects and patients with mild disease [611]. This applied to anti-S pro-
tein and anti-receptor-binding domain (RBD) Abs, that is, Abs
recognizing the S domain binding to the angiotensin-converting enzyme
2 (ACE-2) cell receptor, and to all Ab classes [1215]. The highest levels
of neutralizing Abs, that is, the anti-S Abs identied for their specic
ability to block virus entry in in vitro assays, were found in patients with
more severe illness [15,16]. Serological time course analysis carried out
on hospitalized patients failed to demonstrate a correlation between
anti-S Ab levels and patient outcomes [15]. However, many deceased
patients developed very high levels of anti-S, anti-RBD, and neutralizing
Abs [15,1719]. In addition, the kinetics of the decay of anti-S,
anti-RBD, and neutralizing Abs was strongly correlated [15]. This evi-
dence goes against the hypothesis that the quality, rather than quantity
of Ab response, may predict the patients outcome.
Taken together, these clinical observations raise serious questions
about the correlates of protection against a SARS-CoV-2 infection.
1.2. What is the duration of immune response of anti-S Abs?
The duration of the induced immune response is a critical hallmark
of any vaccine. The humoral immune response relies on the production
of Abs as well as the generation of memory B cells that can undergo
reactivation upon antigen recognition. The duration of the anti-SARS-
CoV-2 antibody response was evaluated for a reasonable time in infec-
ted patients. Conversely, the observation times following vaccine
administration were restricted. Dan and colleagues reported that the
half-life (t
1/2
) of post symptoms onset (PSO) anti-S Abs was 103 days, as
calculated in infected patients tested at least at two time points [3]. The
half-life of anti-RBD Abs was 69 days, and that of neutralizing Abs was
27 days. In these cases, the decay curves were recognized as extended
plateaus. In contrast, the t
1/2
of anti-S and anti-RBD IgAs did not exceed
30 days. In this study, the levels of anti-S humoral response appeared
variable, with more than 2 logs of difference among infected subjects
[3]. In another study, a parallel decay of anti-S, anti-RBD, and neutral-
izing Abs was reported, starting at one to a few months after symptoms
onset, with inpatients developing higher Ab titers than outpatients [15].
This decline was more rapid in asymptomatic and mildly ill patients. In
general, data from Ab levels and kinetics of decay appear inconsistent
among different investigations [3,12,13,15,20,21].
Ab waning may not necessarily imply unresponsiveness in a subse-
quent antigen recognition, considering that humoral immunity can be
promptly reactivated in the presence of a pool of memory B cells. In the
case of SARS-CoV-2 infection, different studies have demonstrated the
persistence of circulating virus-specic memory B cells for up to 8
months [3,2224]. However, the formation of a pool of memory B cells
in airway tissues remains uncertain. Lymphocytes residing in the lungs
are essentially a self-renewing cell population, and this population is
only minimally replenished by circulating cells [25]. Thus, the presence
of virus-specic circulating memory B cells would not necessarily mirror
adequate levels of immunity in lung tissues, which are the region most
involved in SARS-CoV-2 pathogenesis. This may be a critical issue in the
case of anti-SARS-CoV-2 vaccines, since the rapid decrease in Ab
response in the absence of an effective pool of memory B cells in the
lungs may imply the requirement of frequent booster doses.
1.3. Vaccines based on mRNA technology
This is the rst time that vaccines based on mRNA technology have
been proposed for the human population. These vaccine formulations
comprise mRNA molecules where uracil bases are replaced with a
pseudouridine analogue [26] and complexed with hydrophobic lipid
nanoparticles [27] to allow efcient entry into the cells of the injected
host. The lipid nanoparticles are 70100 nm in diameter and are pre-
pared using an ionizable amino lipid, phospholipids, cholesterol, and a
polyethylene glycol (PEG)-ylated lipid [28]. In the case of
anti-SARS-CoV-2 vaccines, mRNA codes for a SARS-CoV-2 S protein with
two proline mutations that stabilize its prefusion conformation [29] in
order to favor the generation of neutralizing Abs. Because of lipid
complexing, injected mRNA molecules can access the cytoplasm of host
cells, thereby initiating S protein synthesis. The viral protein is assumed
to be secreted and recognized by the host immune system as a non-self
product that eventually elicits humoral immunity. When the mRNA
molecules enter an antigen-presenting cell, peptides derived from the
neo-synthesized product may be uploaded to major histocompatibility
complex (MHC) class I molecules, thereby initiating the process leading
to an antiviral CD8
+
T-cell immune response.
A wealth of data supports the conclusion that this strategy leads to a
robust humoral response [3032] associated with apparent protection
from severe symptoms [3335]. To the best of our knowledge,
mRNA-based vaccines do not present major safety concerns, besides
short-term adverse reactions of limited severity. However, at present,
nothing is known about unpredictable, long-term adverse reactions that
could have been monitored only by extended phase III clinical trials. In
addition, the limited observation times preclude a reliable evaluation
regarding the duration of humoral response and need for Ab response
reactivation.
1.4. Vaccines based on human adenoviral vectors
The use of adenoviral vectors is considered the gold standard in
preclinical vaccine experimentation because of the high levels of hu-
moral and cellular immune response against the antigen of interest that
these vectors elicit in animals. This technology has been translated into
anti-SARS-CoV-2 human vaccines with vectors derived from both
human and non-human primate virus strains.
Adenoviruses are non-enveloped, icosahedral viruses approximately
90 nm diameter, with a linear double-stranded DNA genome of 2840
kilobases, expressing 2240 genes depending on the virus type [36].
Human adenoviruses have more than 50 serotypes, divided into seven
species (A to G). Serotypes 2 and 5 are the most widely studied. Ade-
noviruses can infect dividing and non-dividing cells, and have a broad
tropism.
Adenoviral vectors are generally produced in mammalian cells by
recombination between homologous parts of the genome. In classic
laboratory protocols, DNA molecules expressing a replication-defective
adenoviral backbone and a shuttle vector carrying the gene of interest
are co-transfected in mammalian cells, complementing the backbone
defectiveness. Sequences of the gene of interest are transferred to the
viral backbone through recombination, guided by homologous se-
quences present in the two DNA molecules. Adenoviral vectors are
commonly produced by co-transfection in HEK-293 cells engineered to
complement the defectiveness in the viral backbone, most frequently
involving deletions in the E1a, E1b, E3, and E4 genes. In more advanced
technologies, the homologous recombination step occurs in bacteria
[37]. The most popular adenoviral vectors are based on the genomes of
serotypes 5 and 26.
Two aspects should be considered when adenoviral vector-based
technology is applied to human vaccines: (i) the engineered adeno-
viral genome is quite large and expresses, besides the gene of interest,
several additional proteins including capsid proteins II (hexon), III
(penton base), IIIa, IV (ber), VI, VIII, and IX; core proteins V, VII, and X;
and the terminal protein TP, and (ii) adenoviral genomes are prone to
recombination, a feature that can have consequences in the case of non-
human adenoviral vector-based vaccines.
The injection of adenoviral vector particles implies that a single
vaccine administration can generate a widespread immune response
M. Federico
Cytokine and Growth Factor Reviews xxx (xxxx) xxx
3
against the structural adenoviral products. The unavoidable vector-
specic immunity could be minimized by the use of last-generation,
high-capacity adenoviral vectors [38]; however, these have not yet
been approved for clinical use.
Adenovirus infection in immune-competent individuals mostly re-
sults in mild, self-limiting pathologies. It is quite common in humans,
and virus-specic IgGs persist after infection. For instance, 6080% of a
Chinese population had neutralizing Abs against adenovirus serotype 5,
and 2050% had neutralizing Abs against serotype 26 [39]. The data
obtained by analyzing a Brazilian population was consistent with the
ndings of the Chinese population [40]. In another study on individuals
from sub-Saharan Africa, 100 % of persons displayed neutralizing Abs
against serotype 5, and 21 % against serotype 26 [41].
Despite these premises, anti-SARS-CoV-2 vaccines based on adeno-
viral vectors from serotype 5 have been produced and administered
[42]. In some instances, the vaccination schedule includes boosting with
a vector based on serotype 26 [43], which has the advantage of a lower
seroprevalence in humans. In other cases, the vaccination schedule in-
cludes two inoculations with a vector from serotype 26 [44]. Vector
neutralization, ultimately inhibiting the anti-S immune response, is ex-
pected to occur in all subjects already experiencing natural infection
with serotypes 5 and/or 26. In case of uninfected subjects, anti-vector
immunity takes place after the rst immunization, which severely cur-
tails the efcacy of vaccine boosts. Furthermore, the anti-vector im-
munity is also expected to heavily affect possible re-boosting, which is to
be applied after the decay of the immune response induced by the rst
vaccination cycle.
The CD8
+
T-cell response against the diverse adenoviral proteins
that natural infection and vaccine administration can elicit, is also a
hurdle. In this regard, adenovirus-specic CD8
+
T lymphocytes have
been proven to be widespread, polyfunctional, and cross-reactive
against antigens from different human serotypes, as well as from vec-
tors derived from non-human primates [45].
1.5. Vaccines based on non-human adenoviral vectors
In an effort to elude the neutralization effects of pre-existing im-
munity, vaccines based on vectors from non-human primate adenovi-
ruses have been produced and are currently being administered
[4649]. The underlying technology is essentially the same as that used
to produce vaccines based on vectors from human adenoviruses. After
the rst inoculation, anti-vector immunity would strongly decrease the
immunogenicity of these vaccine preparations. Most importantly, the
delivery of non-human adenovirus-based vectors puts vaccine recipients
who were previously infected with human adenoviruses at a risk of
generating new and unpredictable chimeric virus species. In fact,
severely pathogenic virus species may arise as a result of recombination
events. Recombination is quite frequent within adenovirus genomes, as
largely documented by data obtained by sequencing genomes from
people co-infected with different human adenovirus types [5052]. In
vaccinated individuals, a non-human viral vector may enter a single cell
that is already infected with a human adenovirus. Considering the very
high sequence homology between human and non-human primate ad-
enoviruses (>95 %), intracellular recombination events are likely to
occur. Even if at present only theoretical, the likelihood that a similar,
potentially catastrophic event may occur is expected to increase with the
increase in the number of vaccinations.
1.6. Vaccines based on inactivated viruses and recombinant proteins
Anti-SARS-CoV-2 vaccines based on the association of recombinant
trimeric S protein with adjuvants [53], as well as the whole inactivated
virus [54], have also been designed and produced. These approaches
resemble traditional vaccine strategies already applied to ght other
infectious agents, and hence in principle possess high safety proles.
However, issues with Ab efcacy and the duration of immune response
are expected to mirror those already described for the humoral re-
sponses elicited through less conventional vaccine strategies.
2. Conclusions
The major unresolved issue in current anti-SARS-CoV-2 vaccine
strategies is that the immunological correlates of protection against the
virus in humans remain unknown. Results from several clinical obser-
vations are consistent with the idea that the levels of anti-S Abs do not
correlate with patient outcome, and this evidence may have conse-
quences for predicting vaccine efcacy. It is conceivable that quality (e.
g., afnity, avidity, and specicity) rather than quantity of Abs produced
will be critical for virus blockade. More accurate laboratory analyses are
required to validate this hypothesis since, at present, the patient
outcome appears to be independent of the relative amounts of anti-RBD
and neutralizing Abs produced.
A potential obstacle in the development of a SARS-CoV-2 vaccine is
the risk of triggering Ab-dependent enhancement (ADE) of virus infec-
tion and/or immunopathology, as has already been documented for
SARS-CoV [5557] and has been recently suggested for SARS-CoV-2
[5860]. The lack of ADE-related events during the current mass
vaccination tentatively excludes the possibility that some vaccines
might worsen the disease rather than prevent it, as seen with the
Dengvaxia tetravalent yellow fever-dengue Ab-generating vaccine [61].
Vaccine strategies employing adenoviral vectors are controversial in
terms of efcacy and safety. Further, when not already present, as in the
case of vectors based on non-human adenoviruses, the induction of
neutralizing anti-vector immunity seems unavoidable, as also described
in recent clinical trial reports although in sparse and hidden ways [42,
44]. An additional inhibitory mechanism is represented by
vector-specic CD8
+
T-cell immunity. When adenoviral vectors enter
professional and semi-professional antigen-presenting cells, peptides
from viral proteins can associate with MHC class I molecules, thereby
eliciting pools of CD8
+
T lymphocytes that recognize, attack, and
destroy cells expressing the products of adenoviral vectors. These events
would strongly limit the effectiveness of vaccine boosts.
The most alarming perspective pertains to the use of non-human
adenoviral vectors. It is widely accepted that new and aggressive epi-
demics arose from the passage and adaption of viruses from animals to
humans. This was hypothesized, among others, for HIV, avian and swine
inuenza viruses, and, lastly, SARS-CoV-2. In the case of vaccinations
with non-human adenoviral vectors, natural barriers can be overcome
by delivering a non-human viral genome directly into cells. DNA
recombination between different adenovirus species may occur when
the target cells are already infected with a human adenovirus. Since
DNA recombination events are based on the recognition of stretches of
identical sequences, and there is high sequence homology between
human and non-human primate adenoviruses (>95 %), the emergence
of recombinant adenoviruses from vaccinated individuals is, although
rare, a possible event. The positive selection of even a single new
pathogenic adenovirus species would have unpredictable and ungov-
ernable consequences globally.
It is conceivable that protection against SARS-CoV-2 infection would
be the result of the coordinated action of humoral and cellular immu-
nity. Consequently, besides the induction of neutralizing Abs, additional
antiviral preventive strategies should be pursued. Several experimental
and clinical studies prove the benecial effect of virus-specic CD8
+
T-
cell immunity. T cells provide therapeutic benets by directly inducing
lysis of virus-infected cells and shaping the immune response through
the release of cytokines critical for suppressing viral infections. CD8
+
T-
cell responses against respiratory viral infections have been shown to be
as important as humoral responses [6264]. Robust T-cell responses
against S, membrane (M), nucleocapsid (N), and ORF1ab proteins have
been described in COVID-19 convalescent patients [65,66]. The T-cell
response present in asymptomatic and mildly ill infected patients is
absent in severely ill patients [6769]. Notably, CD8
+
T-cell responses
M. Federico
Cytokine and Growth Factor Reviews xxx (xxxx) xxx
4
against S and N protein have been detected in the peripheral blood of
recovered SARS-CoV patients up to 17 years post-infection, in contrast to
the early decay of Ab levels [70].
Novel virus variants harboring mutations in S protein and particu-
larly in the RBD, the target of most neutralizing Abs, are emerging
worldwide. Current vaccines were based on the S protein sequence from
the virus isolated early in the epidemic in Wuhan. Many groups have
published data on vaccine cross-neutralization. Results from two recent
studies based on different in vitro neutralization assays concluded that
current mRNA-based vaccines cross-neutralize both P.1 (Brazil variant)
and B.1.351 (South African variant) poorly [71,72]. Due to the wide-
spread diffusion of the virus, the rapid emergence of mutations is not
surprising. Redesigning vaccines based on new sequences may result in
an element of selective pressure in the case of large-scale vaccinations.
Conversely, a strategy for a universal vaccine including a component
that induces effective CD8
+
T-cell immunity could break such a poten-
tial vicious circle.
Although a strong CD8
+
T-cell response should be a component of
any vaccine regimen for SARS-CoV-2, no reliable vaccine technology for
the induction of cell immunity has been validated for humans to date. In
this regard, adenoviral vectors produced reproducible positive results in
preclinical settings in terms of induction of CD8
+
T-cell immunity in a
wide range of applications. However, results from trials with anti-SARS-
CoV-2 human vaccines appeared modest [39] and, in some cases, elusive
[35].
In conclusion, the extraordinary rapidity of producing diverse anti-
SARS-CoV-2 vaccine options has caused several questions about their
efcacy, duration of immune response, and safety. Intensive basic and
preclinical research is needed to dene pathogenesis, immunopatho-
genesis, and correlates of protection against SARS-CoV-2 infection. This
is the only way to achieve safe and effective preventive and therapeutic
interventions.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgments
No specic grants from funding agencies in the public, commercial,
or not-for-prot sectors pertain to the present manuscript
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tent/10.1101/2021.02.12.430472v1.
Maurizio Federico started his scientic career in the Virology
Laboratory at the Istituto Superiore di Sanit`
a (ISS), Rome, Italy,
headed by Prof. G.B. Rossi. He spent the rst 5 years studying
the antiviral/differentiation effects of interferon, as well as
different molecular aspects of the erythroleukemia differenti-
ation. Afterwards, as part of the Virology laboratory of the
Italian Ministry of Health, he actively contributed to the
isolation and characterization of HIV-1 isolates circulating in
Italy. In this context, he decisively participated to the rst
molecular cloning and sequencing of an HIV-1 isolate from an
Italian patient. In the late90, he became leader of a scientic
team focused on HIV basic research at the Virology Department
of the ISS. Recently, he developed both basic and translational investigations on exosomes
and extracellular vesicles, with the goal to understand their role in HIV-1 pathogenesis. In
addition, these activities represented a starting point for the implementation of an original
platform for the production of CTL vaccines against infectious diseases (included SARS-
CoV-2) and tumors based on the unique molecular characteristics of an HIV-1 Nef
mutant. At the present he acts as Director of the National Center for Global Health at ISS.
M. Federico
... ADE was monitored in human trials and at the start of the large-scale immunization campaign, and the results showed a lack of ADE-related events during the mass vaccination, which tentatively excludes the possibility that some vaccines might worsen the disease rather than improve or even prevent it [81]. ...
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Since December 2019, a pandemic caused by the newly identified SARS-CoV-2 spread across the entire globe, causing 364,191,494 confirmed cases of COVID-19 to date. SARS-CoV-2 is a betacoronavirus, a positive-sense, single-stranded RNA virus with four structural proteins: spike (S), envelope (E), membrane (M), and nucleocapsid (N). The S protein plays a crucial role both in cell binding and in the induction of a strong immune response during COVID-19 infection. The clinical impact of SARS-CoV-2 and its spread led to the urgent need for vaccine development to prevent viral transmission and to reduce the morbidity and mortality associated with the disease. Multiple platforms have been involved in the rapid development of vaccine candidates, with the S protein representing a major target because it can stimulate the immune system, yielding neutralizing antibodies (NAbs), blocking viral entry into host cells, and evoking T-cell immune responses. To date, 178 SARS-CoV-2 vaccine candidates have been challenged in clinical trials, of which 33 were approved by various national regulatory agencies. In this review, we discuss the FDA- and/or EMA-authorized vaccines that are mostly based on mRNA or viral vector platforms. Furthermore, we debunk false myths about the COVID-19 vaccine as well as discuss the impact of viral variants and the possible future developments.
... mortality. These COVID-19 vaccines depend mainly on three pharmaceutical techniques: messenger RNA (mRNA), adenovirus vector, or inactivated SARS-CoV-2 genes [4]. The vaccine based on mRNA (tozinameran) first appeared in 2020 during the COVID-19 pandemic. ...
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Background Several reports have been published about the impact of coronavirus disease 2019 (COVID-19) vaccines on human health, and each vaccine has a different safety and efficacy profile. The aim of this study was to reveal the nature and classification of reported adverse drug reactions (ADRs) of the two COVID-19 vaccines (tozinameran and ChAdOx1) among citizens and residents living in Saudi Arabia, and show possible differences between the two vaccines and the differences between each batch on the health of populations. Methods A cross-sectional study was conducted in Saudi Arabia between December 2020 and March 2021. Saudi citizens and residents aged ≥ 16 years who had at least one dose of any batch of either of the two approved COVID-19 vaccines (tozinameran and ChAdOx1) and who reported at least one ADR from the vaccines were included. The study excluded people who reported ADRs after receiving tozinameran or ChAdOx1 vaccines but no information was provided about the vaccine’s batch number. Results During the study period, 12,868 vaccinated people, including a high-risk group (i.e., those with chronic illness or pregnant women), reported COVID-19 vaccine ADRs that had been documented in the General Directorate of Medical Consultations, Saudi Ministry of Health. The study reported several ADRs associated with COVID-19 vaccines, with the most common (> 25%) being fever/chills, general pain/weakness, headache, and injection site reactions. Among healthy and high-risk people, the median onset of all reported ADRs for tozinameran and ChAdOx1 vaccine batches were 1.96 and 1.64 days, respectively (p < 0.01). Furthermore, significant differences (p < 0.05) were recorded between the two studied vaccines in regard to fever/chills, gastrointestinal symptoms, headache, general pain/weakness, and neurological symptoms, with higher incidence rates of these ADRs observed with the ChAdOx1 vaccine than the tozinameran vaccine. However, the tozinameran vaccine was found to cause significantly (p < 0.05) more palpitation, blood pressure variations, upper respiratory tract symptoms, lymph node swelling, and other unspecified ADRs than the ChAdOx1 vaccine. Among patients vaccinated with seven different batches of the tozinameran vaccine, people vaccinated with the T4 and T5 batches reported the most ADRs. Conclusion There were significant differences regarding most of the reported ADRs and their onset among tozinameran and ChAdOx1 vaccines on both healthy people and high-risk individuals living in Saudi Arabia. Moreover, the study found that the frequencies of most listed ADRs were statistically different when seven batches of tozinameran vaccine were compared.
... Vaccination poses several challenges for SARS-CoV-2 serology because one objective is to determine an antibody concentration that confers full protection against the virus. An ideal immunoassay must quantify the antibodies and provide a binding antibody titer that is correlated with the neutralizing antibody titer (10,11). Serological assays must be able to also measure multiple immunoglobulin classes because the IgM is produced in the early response but does not persist for as long as IgG and IgA, which are long-lasting antibodies (12,13). ...
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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and caused a dramatic pandemic. Serological assays are used to check for immunization and assess herd immunity.
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1. Syndemic identity of COVID-19 pandemic: the experimental child" 2. Limits of the available anti COVID-19 vaccines 3. Genotoxicity of anti-COVID-19 vaccines
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Objectives : Our objective was to determine whether SARS-CoV-2 antibody levels after the first dose can predict the final antibody response and whether this is dependent on the vaccine type. Methods : 69 BNT162b2 (Pfizer/BioNTech) and 55 AZD1222 (AstraZeneca) vaccinees without previous infection or immunosuppressive medication were included. Anti-body levels were quantified 3 weeks after dose 1, in case of AZD1222 directly before boostering (11 weeks after dose 1) and 3 weeks after dose 2, with the Roche SARS-CoV-2 S total antibody assay. Results : Pre-booster (BNT162b2: 80.6 [25.5-167.0] BAU/mL, AZD1222: 56.4 [36.4-104.8] BAU/mL, not significant) and post-booster levels (BNT162b2: 2,092.0 [1,216.3-4,431.8] BAU/mL, AZD1222: 957.0 [684.5-1,684.8] BAU/mL, p<0.0001) correlated well in BNT162b2 (ρ=0.53) but not in AZD1222 recipients. Moreover, antibody levels after the first dose of BNT162b2 correlated inversely with age (ρ=-0.33, P=0.013), whereas a positive correlation with age was observed after the second dose in AZD1222 recipients (ρ=0.26, P=0.030). Conclusions : In conclusion, our data suggest that antibody levels quantified by the Roche Elecsys SARS-CoV-2 S assay before the booster shot could infer post-booster responses to BNT162b2, but not to AZ1222. In addition, we found a vaccine-dependent effect on antibody responses, where age seems to play an ambivalent role.
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p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed<sup>1</sup>. Strong, Th1-skewed T cell responses can drive protective humoral and cell-mediated immune responses<sup>2</sup> and might reduce the potential for disease enhancement<sup>3</sup>. Cytotoxic T cells clear virus-infected host cells and contribute to control of infection<sup>4</sup>. Studies of patients infected with SARS-CoV-2 have suggested a protective role for both humoral and cell-mediated immune responses in recovery from COVID-19 (refs. <sup>5,6</sup>). ChAdOx1 nCoV-19 (AZD1222) is a candidate SARS-CoV-2 vaccine comprising a replication-deficient simian adenovirus expressing full-length SARS-CoV-2 spike protein. We recently reported preliminary safety and immunogenicity data from a phase 1/2 trial of the ChAdOx1 nCoV-19 vaccine (NCT04400838)<sup>7</sup> given as either a one- or two-dose regimen. The vaccine was tolerated, with induction of neutralizing antibodies and antigen-specific T cells against the SARS-CoV-2 spike protein. Here we describe, in detail, exploratory analyses of the immune responses in adults, aged 18–55 years, up to 8 weeks after vaccination with a single dose of ChAdOx1 nCoV-19 in this trial, demonstrating an induction of a Th1-biased response characterized by interferon-γ and tumor necrosis factor-α cytokine secretion by CD4<sup>+</sup> T cells and antibody production predominantly of IgG1 and IgG3 subclasses. CD8<sup>+</sup> T cells, of monofunctional, polyfunctional and cytotoxic phenotypes, were also induced. Taken together, these results suggest a favorable immune profile induced by ChAdOx1 nCoV-19 vaccine, supporting the progression of this vaccine candidate to ongoing phase 2/3 trials to assess vaccine efficacy.</p
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With the recent approval of highly effective COVID-19 vaccines, functional and lasting immunity to SARS-CoV-2 is currently under investigation as antibody levels in plasma were shown to decline during convalescence. Since the absence of antibodies does not equate to absence of immune memory, we evaluate the presence of SARS-CoV-2-specific memory B cells in convalescent individuals. Here we report a longitudinal assessment of humoral immune responses on 32 donors up to 8 months post-symptom onset. Our observations indicate that anti-Spike and anti-RBD IgM in plasma decay rapidly, whereas the reduction of IgG is less prominent. Neutralizing activity also declines rapidly when compared to Fc-effector functions. Concomitantly, the frequencies of RBD-specific IgM+ B cells wane significantly when compared to RBD-specific IgG+ B cells which remain stable. Our results add to the current understanding of immune memory following SARS-CoV-2 infection, which is critical for the prevention of secondary infections and vaccine efficacy.
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p>More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18-55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n = 20) or half-dose (SD/LD D56; n = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials.</p
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Full-text available
Vaccination elicits immune responses capable of potently neutralizing SARS-CoV-2. However, ongoing surveillance has revealed the emergence of variants harboring mutations in spike, the main target of neutralizing antibodies. To understand the impact of globally circulating variants, we evaluated the neutralization potency of 48 sera from BNT162b2 and mRNA-1273 vaccine recipients against pseudoviruses bearing spike proteins derived from 10 strains of SARS- CoV-2. While multiple strains exhibited vaccine-induced cross-neutralization comparable to wild- type pseudovirus, 5 strains harboring receptor-binding domain mutations, including K417N/T, E484K, and N501Y, were highly resistant to neutralization. Cross-neutralization of B.1.351 variants was weak and comparable to SARS-CoV and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. While the clinical impact of neutralization resistance remains uncertain, these results highlight the potential for variants to escape from neutralizing humoral immunity and emphasize the need to develop broadly protective interventions against the evolving pandemic.
Preprint
Full-text available
Large Phase 3 clinical trials of the two FDA-authorized COVID-19 vaccines, mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech), have demonstrated efficacies of 94.1% (n = 30,420, 95% CI: 89.3-96.8) and 95% (n = 43,448, 95% CI: 90.3-97.6) in preventing symptomatic COVID-19, respectively. Given the ongoing vaccine rollout to healthcare personnel and residents of long-term care facilities, here we provide a preliminary assessment of real-world vaccination efficacy in 62,138 individuals from the Mayo Clinic and associated health system (Arizona, Florida, Minnesota, Wisconsin) between December 1st 2020 and February 8th 2021. Our retrospective analysis contrasts 31,069 individuals receiving at least one dose of either vaccine with 31,069 unvaccinated individuals who are propensity-matched based on demographics, location (zip code), and number of prior SARS-CoV-2 PCR tests. 8,041 individuals received two doses of a COVID-19 vaccine and were at risk for infection at least 36 days after their first dose. Administration of two COVID-19 vaccine doses was 88.7% effective in preventing SARS-CoV-2 infection (95% CI: 68.4-97.1%) with onset at least 36 days after the first dose. Furthermore, vaccinated patients who were subsequently diagnosed with COVID-19 had significantly lower 14-day hospital admission rates than propensity-matched unvaccinated COVID-19 patients (3.7% vs. 9.2%; Relative Risk: 0.4; p-value: 0.007). Building upon the previous randomized trials of these vaccines, this study demonstrates their real-world effectiveness in reducing the rates of SARS-CoV-2 infection and COVID-19 severity among individuals at highest risk for infection.
Preprint
Full-text available
Studies on the real-life impact of the BNT162b2 vaccine, recently authorized for the prevention of coronavirus disease 2019 (COVID-19), are urgently needed. Here, we analysed the temporal dynamics of the number of new COVID-19 cases and hospitalization in Israel following a vaccination campaign initiated on December 20th, 2020. We conducted a retrospective analysis of data originating from the Israeli Ministry of Health (MOH) from March 2020 to February 2021. In order to distill the possible effect of the vaccinations from other factors, including a third lockdown imposed in Israel on January 2021, we compared the time-dependent changes in number of COVID-19 cases and hospitalizations between (1) individuals aged 60 years and older, eligible to receive the vaccine earlier and younger individuals (0-59 years old); (2) early-vaccinated cities compared to late-vaccinated cities; (3) early-vaccinated geographical statistical areas (GSAs) compared to late-vaccinated GSAs; and (4) the current lockdown versus the previous lockdown, imposed on September 2020. By February 6th 2021, 45.3% and 29.7% of the entire Israeli population (89.9% and 80% of individuals older than 60 years old) received the first dose or both doses of the vaccine, respectively, or recovered from COVID-19. In mid-January, the number of COVID-19 cases and hospitalization started to decline, with a larger and earlier decrease among older individuals. This trend was more evident in early-vaccinated compared to late-vaccinated cities. Such a pattern was not observed in the previous lockdown. Our analysis demonstrates evidence for the real-life effectiveness of a national vaccination campaign in Israel on the pandemic dynamics. This report reflects a snapshot of a fast-changing situation. However, we believe our findings have major public health implications in the struggle against the COVID-19 pandemic, including the publics perception of the need for and benefit of nationwide vaccination campaigns. More studies aimed at assessing the effectiveness of vaccination both on the individual and on the population level, with larger followup are needed.
Preprint
Since entering the world stage in December of 2019, SARS-CoV-2 has impacted every corner of the globe with over 1.48 million deaths and caused untold economic damage. Infections in humans range from asymptomatic to severe disease associated with dysregulation of the immune system leading to the development of acute respiratory distress syndrome (ARDs). The distinct shift in peripheral monocyte activation and infiltration of these cells into the respiratory tract in ARDs patients suggests severe COVID-19 may largely result from damage to the respiratory epithelia by improperly activated macrophages. Here, we present evidence that dysregulation of the immune response in COVID-19 begins with activation of macrophages by non-neutralizing antibodies and induction of ACE2 expression, rendering these cells susceptible to killing by SARS-CoV-2. Death of macrophages occurs independently of viral replication and leads to the release of inflammatory mediators and modulation of the susceptibility of downstream epithelial cells to SARS-CoV-2.