The conundrum of current anti-SARS-CoV-2 vaccines

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 protection” refers 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 [6–11]. 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 [12–15]. 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 [15,17–19]. 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 patient’s 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 [3,22–24]. 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 70–100 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 [30–32] associated with apparent protection
from severe symptoms [33–35]. 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 28–40
kilobases, expressing 22–40 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
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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, 60–80% of a
Chinese population had neutralizing Abs against adenovirus serotype 5,
and 20–50% 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
[46–49]. 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 [50–52]. 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 [55–57] and has been recently suggested for SARS-CoV-2
[58–60]. 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 [62–64]. 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 [67–69]. 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
References
[1] COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at
Johns Hopkins University (JHU) https://coronavirus.jhu.edu/map.html.
[2] S.A. Plotkin, Vaccines: correlates of vaccine-induced immunity, Clin. Infect. Dis. 47
(2008) 401–409, https://doi.org/10.1086/589862.
[3] J.M. Dan, J. Mateus, Y. Kato, K.M. Hastie, E.D. Yu, C.E. Faliti, A. Grifoni, S.
I. Ramirez, S. Haupt, A. Frazier, C. Nakao, V. Rayaprolu, S.A. Rawlings, B. Peters,
F. Krammer, V. Simon, E.O. Saphire, D.M. Smith, D. Weiskopf, A. Sette, S. Crotty,
Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection,
Science (2021), https://doi.org/10.1126/science.abf4063.
[4] A. Sette, S. Crotty, Adaptive immunity to SARS-CoV-2 and COVID-19, Cell (2021),
https://doi.org/10.1016/j.cell.2021.01.007.
[5] K. McMahan, J. Yu, N.B. Mercado, C. Loos, L.H. Tostanoski, A. Chandrashekar,
J. Liu, L. Peter, C. Atyeo, A. Zhu, E.A. Bondzie, G. Dagotto, M.S. Gebre, C. Jacob-
Dolan, Z. Li, F. Nampanya, S. Patel, L. Pessaint, A. Van Ry, K. Blade, J. Yalley-
Ogunro, M. Cabus, R. Brown, A. Cook, E. Teow, H. Andersen, M.G. Lewis, D.
A. Lauffenburger, G. Alter, D.H. Barouch, Correlates of protection against SARS-
CoV-2 in rhesus macaques, Nature (2020), https://doi.org/10.1038/s41586-020-
03041-6.
[6] I.F.-N. Hung, V.C.-C. Cheng, X. Li, A.R. Tam, D.L.-L. Hung, K.H.-Y. Chiu, C.C.-
Y. Yip, J.-P. Cai, D.T.-Y. Ho, S.-C. Wong, S.S.-M. Leung, M.-Y. Chu, M.O.-Y. Tang, J.
H.-K. Chen, R.W.-S. Poon, A.Y.-F. Fung, R.R. Zhang, E.Y.-W. Yan, L.-L. Chen, C.Y.-
K. Choi, K.-H. Leung, T.W.-H. Chung, S.H.-Y. Lam, T.P.-W. Lam, J.F.-W. Chan, K.-
H. Chan, T.-C. Wu, P.-L. Ho, J.W.-M. Chan, C.-S. Lau, K.K.-W. To, K.-Y. Yuen, SARS-
CoV-2 shedding and seroconversion among passengers quarantined after
disembarking a cruise ship: a case series, Lancet Infect. Dis. 20 (2020) 1051–1060,
https://doi.org/10.1016/S1473-3099(20)30364-9.
[7] Q.-X. Long, X.-J. Tang, Q.-L. Shi, Q. Li, H.-J. Deng, J. Yuan, J.-L. Hu, W. Xu,
Y. Zhang, F.-J. Lv, K. Su, F. Zhang, J. Gong, B. Wu, X.-M. Liu, J.-J. Li, J.-F. Qiu,
J. Chen, A.-L. Huang, Clinical and immunological assessment of asymptomatic
SARS-CoV-2 infections, Nat. Med. 26 (2020) 1200–1204, https://doi.org/10.1038/
s41591-020-0965-6.
[8] T.J. Ripperger, J.L. Uhrlaub, M. Watanabe, R. Wong, Y. Castaneda, H.A. Pizzato, M.
R. Thompson, C. Bradshaw, C.C. Weinkauf, C. Bime, H.L. Erickson, K. Knox,
B. Bixby, S. Parthasarathy, S. Chaudhary, B. Natt, E. Cristan, T. El Aini, F. Rischard,
J. Campion, M. Chopra, M. Insel, A. Sam, J.L. Knepler, A.P. Capaldi, C.M. Spier, M.
D. Dake, T. Edwards, M.E. Kaplan, S.J. Scott, C. Hypes, J. Mosier, D.T. Harris, B.
J. LaFleur, R. Sprissler, J. Nikolich-ˇ
Zugich, D. Bhattacharya, Orthogonal SARS-
CoV-2 serological assays enable surveillance of low-prevalence communities and
reveal durable humoral immunity, Immunity 53 (2020) 925–933, https://doi.org/
10.1016/j.immuni.2020.10.004, e4.
[9] Y. Wang, L. Zhang, L. Sang, F. Ye, S. Ruan, B. Zhong, T. Song, A.N. Alshukairi,
R. Chen, Z. Zhang, M. Gan, A. Zhu, Y. Huang, L. Luo, C.K.P. Mok, M.M. Al
Gethamy, H. Tan, Z. Li, X. Huang, F. Li, J. Sun, Y. Zhang, L. Wen, Y. Li, Z. Chen,
Z. Zhuang, J. Zhuo, C. Chen, L. Kuang, J. Wang, H. Lv, Y. Jiang, M. Li, Y. Lin,
Y. Deng, L. Tang, J. Liang, J. Huang, S. Perlman, N. Zhong, J. Zhao, J.S. Malik
Peiris, Y. Li, J. Zhao, Kinetics of viral load and antibody response in relation to
COVID-19 severity, J. Clin. Invest. 130 (2020) 5235–5244, https://doi.org/
10.1172/JCI138759.
[10] M.C. Woodruff, R.P. Ramonell, D.C. Nguyen, K.S. Cashman, A.S. Saini, N.
S. Haddad, A.M. Ley, S. Kyu, J.C. Howell, T. Ozturk, S. Lee, N. Suryadevara, J.
B. Case, R. Bugrovsky, W. Chen, J. Estrada, A. Morrison-Porter, A. Derrico, F.
A. Anam, M. Sharma, H.M. Wu, S.N. Le, S.A. Jenks, C.M. Tipton, B. Staitieh, J.
L. Daiss, E. Ghosn, M.S. Diamond, R.H. Carnahan, J.E. Crowe, W.T. Hu, F.E.-H. Lee,
I. Sanz, Extrafollicular B cell responses correlate with neutralizing antibodies and
morbidity in COVID-19, Nat. Immunol. 21 (2020) 1506–1516, https://doi.org/
10.1038/s41590-020-00814-z.
[11] A.T. Tan, M. Linster, C.W. Tan, N. Le Bert, W.N. Chia, K. Kunasegaran, Y. Zhuang,
C.Y.L. Tham, A. Chia, G.J.D. Smith, B. Young, S. Kalimuddin, J.G.H. Low, D. Lye,
L.-F. Wang, A. Bertoletti, Early induction of functional SARS-CoV-2-specic T cells
associates with rapid viral clearance and mild disease in COVID-19 patients, Cell
Rep. (2021) 108728, https://doi.org/10.1016/j.celrep.2021.108728.
[12] L. Piccoli, Y.-J. Park, M.A. Tortorici, N. Czudnochowski, A.C. Walls,
M. Beltramello, C. Silacci-Fregni, D. Pinto, L.E. Rosen, J.E. Bowen, O.J. Acton,
S. Jaconi, B. Guarino, A. Minola, F. Zatta, N. Sprugasci, J. Bassi, A. Peter, A. De
Marco, J.C. Nix, F. Mele, S. Jovic, B.F. Rodriguez, S.V. Gupta, F. Jin, G. Piumatti,
G. Lo Presti, A.F. Pellanda, M. Biggiogero, M. Tarkowski, M.S. Pizzuto,
E. Cameroni, C. Havenar-Daughton, M. Smithey, D. Hong, V. Lepori, E. Albanese,
A. Ceschi, E. Bernasconi, L. Elzi, P. Ferrari, C. Garzoni, A. Riva, G. Snell, F. Sallusto,
K. Fink, H.W. Virgin, A. Lanzavecchia, D. Corti, D. Veesler, Mapping neutralizing
and immunodominant sites on the SARS-CoV-2 spike receptor-binding domain by
structure-guided high-resolution serology, Cell 183 (2020) 1024–1042, https://
doi.org/10.1016/j.cell.2020.09.037, e21.
[13] D.F. Robbiani, C. Gaebler, F. Muecksch, J.C.C. Lorenzi, Z. Wang, A. Cho,
M. Agudelo, C.O. Barnes, A. Gazumyan, S. Finkin, T. H¨
aggl¨
of, T.Y. Oliveira,
C. Viant, A. Hurley, H.-H. Hoffmann, K.G. Millard, R.G. Kost, M. Cipolla,
K. Gordon, F. Bianchini, S.T. Chen, V. Ramos, R. Patel, J. Dizon, I. Shimeliovich,
P. Mendoza, H. Hartweger, L. Nogueira, M. Pack, J. Horowitz, F. Schmidt,
Y. Weisblum, E. Michailidis, A.W. Ashbrook, E. Waltari, J.E. Pak, K.E. Huey-
Tubman, N. Koranda, P.R. Hoffman, A.P. West, C.M. Rice, T. Hatziioannou, P.
J. Bjorkman, P.D. Bieniasz, M. Caskey, M.C. Nussenzweig, Convergent antibody
responses to SARS-CoV-2 in convalescent individuals, Nature 584 (2020) 437–442,
https://doi.org/10.1038/s41586-020-2456-9.
[14] S.P. Anand, J. Pr´
evost, M. Nayrac, G. Beaudoin-Bussi`
eres, M. Benlarbi, R. Gasser,
N. Brassard, A. Laumaea, S.Y. Gong, C. Bourassa, E. Brunet-Ratnasingham,
H. Medjahed, G. Gendron-Lepage, G. Goyette, L. Gokool, C. Morrisseau, P. B´
egin,
V. Martel-Laferri`
ere, C. Tremblay, J. Richard, R. Bazin, R. Duerr, D.E. Kaufmann,
A. Finzi, Longitudinal analysis of humoral immunity against SARS-CoV-2 Spike in
convalescent individuals up to 8 months post-symptom onset, BioRxiv (2021),
https://doi.org/10.1101/2021.01.25.428097.
[15] K. R¨
oltgen, A.E. Powell, O.F. Wirz, B.A. Stevens, C.A. Hogan, J. Najeeb, M. Hunter,
H. Wang, M.K. Sahoo, C. Huang, F. Yamamoto, M. Manohar, J. Manalac, A.
R. Otrelo-Cardoso, T.D. Pham, A. Rustagi, A.J. Rogers, N.H. Shah, C.A. Blish, J.
R. Cochran, T.S. Jardetzky, J.L. Zehnder, T.T. Wang, B. Narasimhan, S. Gombar,
R. Tibshirani, K.C. Nadeau, P.S. Kim, B.A. Pinsky, S.D. Boyd, Dening the features
and duration of antibody responses to SARS-CoV-2 infection associated with
disease severity and outcome, Sci. Immunol. 5 (2020), https://doi.org/10.1126/
sciimmunol.abe0240.
[16] C. Rydyznski Moderbacher, S.I. Ramirez, J.M. Dan, A. Grifoni, K.M. Hastie,
D. Weiskopf, S. Belanger, R.K. Abbott, C. Kim, J. Choi, Y. Kato, E.G. Crotty, C. Kim,
S.A. Rawlings, J. Mateus, L.P.V. Tse, A. Frazier, R. Baric, B. Peters, J. Greenbaum,
E. Ollmann Saphire, D.M. Smith, A. Sette, S. Crotty, Antigen-specic adaptive
immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease
severity, Cell 183 (2020) 996–1012, https://doi.org/10.1016/j.cell.2020.09.038,
e19.
[17] C. Atyeo, S. Fischinger, T. Zohar, M.D. Slein, J. Burke, C. Loos, D.J. McCulloch, K.
L. Newman, C. Wolf, J. Yu, K. Shuey, J. Feldman, B.M. Hauser, T. Caradonna, A.
G. Schmidt, T.J. Suscovich, C. Linde, Y. Cai, D. Barouch, E.T. Ryan, R.C. Charles,
D. Lauffenburger, H. Chu, G. Alter, Distinct early serological signatures track with
SARS-CoV-2 survival, Immunity 53 (2020) 524–532, https://doi.org/10.1016/j.
immuni.2020.07.020, e4.
[18] Q.-X. Long, B.-Z. Liu, H.-J. Deng, G.-C. Wu, K. Deng, Y.-K. Chen, P. Liao, J.-F. Qiu,
Y. Lin, X.-F. Cai, D.-Q. Wang, Y. Hu, J.-H. Ren, N. Tang, Y.-Y. Xu, L.-H. Yu, Z. Mo,
F. Gong, X.-L. Zhang, W.-G. Tian, L. Hu, X.-X. Zhang, J.-L. Xiang, H.-X. Du, H.-
W. Liu, C.-H. Lang, X.-H. Luo, S.-B. Wu, X.-P. Cui, Z. Zhou, M.-M. Zhu, J. Wang, C.-
M. Federico

Cytokine and Growth Factor Reviews xxx (xxxx) xxx
5
J. Xue, X.-F. Li, L. Wang, Z.-J. Li, K. Wang, C.-C. Niu, Q.-J. Yang, X.-J. Tang,
Y. Zhang, X.-M. Liu, J.-J. Li, D.-C. Zhang, F. Zhang, P. Liu, J. Yuan, Q. Li, J.-L. Hu,
J. Chen, A.-L. Huang, Antibody responses to SARS-CoV-2 in patients with COVID-
19, Nat. Med. 26 (2020) 845–848, https://doi.org/10.1038/s41591-020-0897-1.
[19] A. Flemming, Deciphering the protective features of the antibody response, Nat.
Rev. Immunol. 70 (21) (2021), https://doi.org/10.1038/s41577-020-00496-6.
[20] D.F. Gudbjartsson, G.L. Norddahl, P. Melsted, K. Gunnarsdottir, H. Holm,
E. Eythorsson, et al., Humoral immune response to SARS-CoV-2 in Iceland, N. Engl.
J. Med. 383 (2020) 1724–1734, https://doi.org/10.1056/NEJMoa2026116.
[21] B. Sun, Y. Feng, X. Mo, P. Zheng, Q. Wang, P. Li, P. Peng, X. Liu, Z. Chen, H. Huang,
F. Zhang, W. Luo, X. Niu, P. Hu, L. Wang, H. Peng, Z. Huang, L. Feng, F. Li,
F. Zhang, F. Li, N. Zhong, L. Chen, Kinetics of SARS-CoV-2 specic IgM and IgG
responses in COVID-19 patients, Emerg. Microbes Infect. 9 (2020) 940–948,
https://doi.org/10.1080/22221751.2020.1762515.
[22] L.B. Rodda, J. Netland, L. Shehata, K.B. Pruner, P.A. Morawski, C.D. Thouvenel, K.
K. Takehara, J. Eggenberger, E.A. Hemann, H.R. Waterman, M.L. Fahning, Y. Chen,
M. Hale, J. Rathe, C. Stokes, S. Wrenn, B. Fiala, L. Carter, J.A. Hamerman, N.
P. King, M. Gale, D.J. Campbell, D.J. Rawlings, M. Pepper, Functional SARS-CoV-2-
Specic immune memory persists after mild COVID-19, Cell 184 (2021) 169–183,
https://doi.org/10.1016/j.cell.2020.11.029, e17.
[23] C. Gaebler, Z. Wang, J.C.C. Lorenzi, F. Muecksch, S. Finkin, M. Tokuyama, A. Cho,
M. Jankovic, D. Schaefer-Babajew, T.Y. Oliveira, M. Cipolla, C. Viant, C.O. Barnes,
Y. Bram, G. Breton, T. H¨
aggl¨
of, P. Mendoza, A. Hurley, M. Turroja, K. Gordon, K.
G. Millard, V. Ramos, F. Schmidt, Y. Weisblum, D. Jha, M. Tankelevich,
G. Martinez-Delgado, J. Yee, R. Patel, J. Dizon, C. Unson-O’Brien, I. Shimeliovich,
D.F. Robbiani, Z. Zhao, A. Gazumyan, R.E. Schwartz, T. Hatziioannou, P.
J. Bjorkman, S. Mehandru, P.D. Bieniasz, M. Caskey, M.C. Nussenzweig, Evolution
of antibody immunity to SARS-CoV-2, Nature (2021), https://doi.org/10.1038/
s41586-021-03207-w.
[24] I. Quast, D. Tarlinton, B cell memory: understanding COVID-19, Immunity 54
(2021) 205–210, https://doi.org/10.1016/j.immuni.2021.01.014.
[25] J.E. Kohlmeier, D.L. Woodland, Immunity to respiratory viruses, Annu. Rev.
Immunol. 27 (2009) 61–82, https://doi.org/10.1146/annurev.
immunol.021908.132625.
[26] K. Karik´
o, H. Muramatsu, F.A. Welsh, J. Ludwig, H. Kato, S. Akira, D. Weissman,
Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector
with increased translational capacity and biological stability, Mol. Ther. 16 (2008)
1833–1840, https://doi.org/10.1038/mt.2008.200.
[27] N. Pardi, S. Tuyishime, H. Muramatsu, K. Kariko, B.L. Mui, Y.K. Tam, T.D. Madden,
M.J. Hope, D. Weissman, Expression kinetics of nucleoside-modied mRNA
delivered in lipid nanoparticles to mice by various routes, J. Control. Release 217
(2015) 345–351, https://doi.org/10.1016/j.jconrel.2015.08.007.
[28] M.A. Maier, M. Jayaraman, S. Matsuda, J. Liu, S. Barros, W. Querbes, Y.K. Tam, S.
M. Ansell, V. Kumar, J. Qin, X. Zhang, Q. Wang, S. Panesar, R. Hutabarat,
M. Carioto, J. Hettinger, P. Kandasamy, D. Butler, K.G. Rajeev, B. Pang,
K. Charisse, K. Fitzgerald, B.L. Mui, X. Du, P. Cullis, T.D. Madden, M.J. Hope,
M. Manoharan, A. Akinc, Biodegradable lipids enabling rapidly eliminated lipid
nanoparticles for systemic delivery of RNAi therapeutics, Mol. Ther. 21 (2013)
1570–1578, https://doi.org/10.1038/mt.2013.124.
[29] D. Wrapp, N. Wang, K.S. Corbett, J.A. Goldsmith, C.-L. Hsieh, O. Abiona, B.
S. Graham, J.S. McLellan, Cryo-EM structure of the 2019-nCoV spike in the
prefusion conformation, Science 367 (2020) 1260–1263, https://doi.org/10.1126/
science.abb2507.
[30] E.E. Walsh, R.W. Frenck, A.R. Falsey, N. Kitchin, J. Absalon, A. Gurtman,
S. Lockhart, K. Neuzil, M.J. Mulligan, R. Bailey, K.A. Swanson, P. Li, K. Koury,
W. Kalina, D. Cooper, C. Fontes-Garas, P.-Y. Shi, ¨
O. Türeci, K.R. Tompkins, K.
E. Lyke, V. Raabe, P.R. Dormitzer, K.U. Jansen, U. S
¸ahin, W.C. Gruber, Safety and
immunogenicity of two RNA-Based Covid-19 vaccine candidates, N. Engl. J. Med.
383 (2020) 2439–2450, https://doi.org/10.1056/NEJMoa2027906.
[31] L.A. Jackson, E.J. Anderson, N.G. Rouphael, P.C. Roberts, M. Makhene, R.N. Coler,
M.P. McCullough, J.D. Chappell, M.R. Denison, L.J. Stevens, A.J. Pruijssers,
A. McDermott, B. Flach, N.A. Doria-Rose, K.S. Corbett, K.M. Morabito, S. O’Dell, S.
D. Schmidt, P.A. Swanson, M. Padilla, J.R. Mascola, K.M. Neuzil, H. Bennett,
W. Sun, E. Peters, M. Makowski, J. Albert, K. Cross, W. Buchanan, R. Pikaart-
Tautges, J.E. Ledgerwood, B.S. Graham, J.H. Beigel, mRNA-1273 Study Group, An
mRNA Vaccine against SARS-CoV-2 - Preliminary Report, N. Engl. J. Med. 383
(2020) 1920–1931, https://doi.org/10.1056/NEJMoa2022483.
[32] E.J. Anderson, N.G. Rouphael, A.T. Widge, L.A. Jackson, P.C. Roberts,
M. Makhene, J.D. Chappell, M.R. Denison, L.J. Stevens, A.J. Pruijssers, A.
B. McDermott, B. Flach, B.C. Lin, N.A. Doria-Rose, S. O’Dell, S.D. Schmidt, K.
S. Corbett, P.A. Swanson, M. Padilla, K.M. Neuzil, H. Bennett, B. Leav,
M. Makowski, J. Albert, K. Cross, V.V. Edara, K. Floyd, M.S. Suthar, D.R. Martinez,
R. Baric, W. Buchanan, C.J. Luke, V.K. Phadke, C.A. Rostad, J.E. Ledgerwood, B.
S. Graham, J.H. Beigel, mRNA-1273 study group, safety and immunogenicity of
SARS-CoV-2 mRNA-1273 vaccine in older adults, N. Engl. J. Med. 383 (2020)
2427–2438, https://doi.org/10.1056/NEJMoa2028436.
[33] S. Amit, G. Regev-Yochay, A. Afek, Y. Kreiss, E. Leshem, Early rate reductions of
SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients, Lancet
(2021), https://doi.org/10.1016/S0140-6736(21)00448-7.
[34] H. Rossman, S. Shilo, T. Meir, M. Gorne, U. Shalit, E. Segal, Patterns of COVID-19
pandemic dynamics following deployment of a broad national immunization
program, MedRxiv (2021), https://doi.org/10.1101/2021.02.08.21251325,
2021.02.08.21251325.
[35] C. Pawlowski, P. Lenehan, A. Puranik, V. Agarwal, A.J. Venkatakrishnan, M.
J. Niesen, J.C.O. Horo, A.D. Badley, J. Halamka, V. Soundararajan, FDA-authorized
COVID-19 vaccines are effective per real-world evidence synthesized across a
multi-state health system, MedRxiv (2021), https://doi.org/10.1101/
2021.02.15.21251623, 2021.02.15.21251623.
[36] G. Nemerow, J. Flint, Lessons learned from adenovirus (1970–2019), FEBS Lett.
593 (2019) 3395–3418, https://doi.org/10.1002/1873-3468.13700.
[37] I. Khatun, Adenoviral Vectors, Materials and Methods, 2020. /method/Adenoviral-
Vectors.html.
[38] A. Ricobaraza, M. Gonzalez-Aparicio, L. Mora-Jimenez, S. Lumbreras,
R. Hernandez-Alcoceba, High-capacity adenoviral vectors: expanding the scope of
gene therapy, Int. J. Mol. Sci. 21 (2020), https://doi.org/10.3390/ijms21103643.
[39] S. Zhang, W. Huang, X. Zhou, Q. Zhao, Q. Wang, B. Jia, Seroprevalence of
neutralizing antibodies to human adenoviruses type-5 and type-26 and chimpanzee
adenovirus type-68 in healthy Chinese adults, J. Med. Virol. 85 (2013) 1077–1084,
https://doi.org/10.1002/jmv.23546.
[40] J. Ersching, M.I.M. Hernandez, F.S. Cezarotto, J.D.S. Ferreira, A.B. Martins, W.
M. Switzer, Z. Xiang, H.C.J. Ertl, C.R. Zanetti, A.R. Pinto, Neutralizing antibodies to
human and simian adenoviruses in humans and New-World monkeys, Virology 407
(2010) 1–6, https://doi.org/10.1016/j.virol.2010.07.043.
[41] P. Abbink, A.A.C. Lemckert, B.A. Ewald, D.M. Lynch, M. Denholtz, S. Smits,
L. Holterman, I. Damen, R. Vogels, A.R. Thorner, K.L. O’Brien, A. Carville, K.
G. Manseld, J. Goudsmit, M.J.E. Havenga, D.H. Barouch, Comparative
seroprevalence and immunogenicity of six rare serotype recombinant adenovirus
vaccine vectors from subgroups B and D, J. Virol. 81 (2007) 4654–4663, https://
doi.org/10.1128/JVI.02696-06.
[42] F.-C. Zhu, X.-H. Guan, Y.-H. Li, J.-Y. Huang, T. Jiang, L.-H. Hou, J.-X. Li, B.-F. Yang,
L. Wang, W.-J. Wang, S.-P. Wu, Z. Wang, X.-H. Wu, J.-J. Xu, Z. Zhang, S.-Y. Jia, B.-
S. Wang, Y. Hu, J.-J. Liu, J. Zhang, X.-A. Qian, Q. Li, H.-X. Pan, H.-D. Jiang,
P. Deng, J.-B. Gou, X.-W. Wang, X.-H. Wang, W. Chen, Immunogenicity and safety
of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults
aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2
trial, Lancet 396 (2020) 479–488, https://doi.org/10.1016/S0140-6736(20)
31605-6.
[43] D.Y. Logunov, I.V. Dolzhikova, O.V. Zubkova, A.I. Tukhvatulin, D.
V. Shcheblyakov, A.S. Dzharullaeva, D.M. Grousova, A.S. Erokhova, A.
V. Kovyrshina, A.G. Botikov, F.M. Izhaeva, O. Popova, T.A. Ozharovskaya, I.
B. Esmagambetov, I.A. Favorskaya, D.I. Zrelkin, D.V. Voronina, D.N. Shcherbinin,
A.S. Semikhin, Y.V. Simakova, E.A. Tokarskaya, N.L. Lubenets, D.A. Egorova, M.
M. Shmarov, N.A. Nikitenko, L.F. Morozova, E.A. Smolyarchuk, E.V. Kryukov, V.
F. Babira, S.V. Borisevich, B.S. Naroditsky, A.L. Gintsburg, Safety and
immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost
COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2
studies from Russia, Lancet 396 (2020) 887–897, https://doi.org/10.1016/S0140-
6736(20)31866-3.
[44] J. Sadoff, M. Le Gars, G. Shukarev, D. Heerwegh, C. Truyers, A.M. de Groot,
J. Stoop, S. Tete, W. Van Damme, I. Leroux-Roels, P.-J. Berghmans, M. Kimmel,
P. Van Damme, J. de Hoon, W. Smith, K.E. Stephenson, S.C. De Rosa, K.W. Cohen,
M.J. McElrath, E. Cormier, G. Scheper, D.H. Barouch, J. Hendriks, F. Struyf,
M. Douoguih, J. Van Hoof, H. Schuitemaker, Interim results of a phase 1-2a trial of
Ad26.COV2.S Covid-19 vaccine, N. Engl. J. Med. (2021), https://doi.org/10.1056/
NEJMoa2034201.
[45] N.A. Hutnick, D. Carnathan, K. Demers, G. Makedonas, H.C.J. Ertl, M.R. Betts,
Adenovirus-specic human T cells are pervasive, polyfunctional, and cross-
reactive, Vaccine 28 (2010) 1932–1941, https://doi.org/10.1016/j.
vaccine.2009.10.091.
[46] K.J. Ewer, J.R. Barrett, S. Belij-Rammerstorfer, H. Sharpe, R. Makinson, R. Morter,
A. Flaxman, D. Wright, D. Bellamy, M. Bittaye, C. Dold, N.M. Provine, J. Aboagye,
J. Fowler, S.E. Silk, J. Alderson, P.K. Aley, B. Angus, E. Berrie, S. Bibi, P. Cicconi, E.
A. Clutterbuck, I. Chelysheva, P.M. Folegatti, M. Fuskova, C.M. Green, D. Jenkin,
S. Kerridge, A. Lawrie, A.M. Minassian, M. Moore, Y. Mujadidi, E. Plested,
I. Poulton, M.N. Ramasamy, H. Robinson, R. Song, M.D. Snape, R. Tarrant,
M. Voysey, M.E.E. Watson, A.D. Douglas, A.V.S. Hill, S.C. Gilbert, A.J. Pollard,
T. Lambe, Oxford COVID Vaccine Trial Group, T cell and antibody responses
induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2
clinical trial, Nat. Med. (2020), https://doi.org/10.1038/s41591-020-01194-5.
[47] J.R. Barrett, S. Belij-Rammerstorfer, C. Dold, K.J. Ewer, P.M. Folegatti, C. Gilbride,
R. Halkerston, J. Hill, D. Jenkin, L. Stockdale, M.K. Verheul, P.K. Aley, B. Angus,
D. Bellamy, E. Berrie, S. Bibi, M. Bittaye, M.W. Carroll, B. Cavell, E.A. Clutterbuck,
N. Edwards, A. Flaxman, M. Fuskova, A. Gorringe, B. Hallis, S. Kerridge, A.
M. Lawrie, A. Linder, X. Liu, M. Madhavan, R. Makinson, J. Mellors, A. Minassian,
M. Moore, Y. Mujadidi, E. Plested, I. Poulton, M.N. Ramasamy, H. Robinson, C.
S. Rollier, R. Song, M.D. Snape, R. Tarrant, S. Taylor, K.M. Thomas, M. Voysey, M.
E.E. Watson, D. Wright, A.D. Douglas, C.M. Green, A.V.S. Hill, T. Lambe, S. Gilbert,
A.J. Pollard, Oxford COVID Vaccine Trial Group, Phase 1/2 trial of SARS-CoV-2
vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody
responses, Nat. Med. (2020), https://doi.org/10.1038/s41591-020-01179-4.
[48] M. Voysey, S.A. Costa Clemens, S.A. Madhi, L.Y. Weckx, P.M. Folegatti, P.K. Aley,
et al., Safety and efcacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against
SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil,
South Africa, and the UK, Lancet 397 (2012) 99–111, https://doi.org/10.1016/
S0140-6736(20)32661-1.
[49] M.N. Ramasamy, A.M. Minassian, K.J. Ewer, A.L. Flaxman, P.M. Folegatti, D.
R. Owens, M. Voysey, P.K. Aley, B. Angus, G. Babbage, S. Belij-Rammerstorfer,
L. Berry, S. Bibi, M. Bittaye, K. Cathie, H. Chappell, S. Charlton, P. Cicconi, E.
A. Clutterbuck, R. Colin-Jones, C. Dold, K.R.W. Emary, S. Fedosyuk, M. Fuskova,
D. Gbesemete, C. Green, B. Hallis, M.M. Hou, D. Jenkin, C.C.D. Joe, E.J. Kelly,
S. Kerridge, A.M. Lawrie, A. Lelliott, M.N. Lwin, R. Makinson, N.G. Marchevsky,
Y. Mujadidi, A.P.S. Munro, M. Pacurar, E. Plested, J. Rand, T. Rawlinson, S. Rhead,
M. Federico

Cytokine and Growth Factor Reviews xxx (xxxx) xxx
6
H. Robinson, A.J. Ritchie, A.L. Ross-Russell, S. Saich, N. Singh, C.C. Smith, M.
D. Snape, R. Song, R. Tarrant, Y. Themistocleous, K.M. Thomas, T.L. Villafana, S.
C. Warren, M.E.E. Watson, A.D. Douglas, A.V.S. Hill, T. Lambe, S.C. Gilbert, S.
N. Faust, A.J. Pollard, Oxford COVID Vaccine Trial Group, Safety and
immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost
regimen in young and old adults (COV002): a single-blind, randomised, controlled,
phase 2/3 trial, Lancet 396 (2021) 1979–1993, https://doi.org/10.1016/S0140-
6736(20)32466-1.
[50] J. Yu, S. Zhao, H. Rao, Whole genomic analysis of a potential recombinant human
adenovirus type 1 in Qinghai plateau, China, Virol. J. 17 (2020) 111, https://doi.
org/10.1186/s12985-020-01387-x.
[51] W. Zhang, L. Huang, Genome analysis of a novel recombinant human adenovirus
type 1 in China, Sci. Rep. 9 (2019) 4298, https://doi.org/10.1038/s41598-018-
37756-4.
[52] Y. Wang, Y. Li, R. Lu, Y. Zhao, Z. Xie, J. Shen, W. Tan, Phylogenetic evidence for
intratypic recombinant events in a novel human adenovirus C that causes severe
acute respiratory infection in children, Sci. Rep. 6 (2016) 23014, https://doi.org/
10.1038/srep23014.
[53] C. Keech, G. Albert, I. Cho, A. Robertson, P. Reed, S. Neal, J.S. Plested, M. Zhu,
S. Cloney-Clark, H. Zhou, G. Smith, N. Patel, M.B. Frieman, R.E. Haupt, J. Logue,
M. McGrath, S. Weston, P.A. Piedra, C. Desai, K. Callahan, M. Lewis, P. Price-
Abbott, N. Formica, V. Shinde, L. Fries, J.D. Lickliter, P. Grifn, B. Wilkinson, G.
M. Glenn, Phase 1-2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle
vaccine, N. Engl. J. Med. 383 (2020) 2320–2332, https://doi.org/10.1056/
NEJMoa2026920.
[54] S. Xia, Y. Zhang, Y. Wang, H. Wang, Y. Yang, G.F. Gao, W. Tan, G. Wu, M. Xu,
Z. Lou, W. Huang, W. Xu, B. Huang, H. Wang, W. Wang, W. Zhang, N. Li, Z. Xie,
L. Ding, W. You, Y. Zhao, X. Yang, Y. Liu, Q. Wang, L. Huang, Y. Yang, G. Xu,
B. Luo, W. Wang, P. Liu, W. Guo, X. Yang, Safety and immunogenicity of an
inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind,
placebo-controlled, phase 1/2 trial, Lancet Infect. Dis. 21 (2021) 39–51, https://
doi.org/10.1016/S1473-3099(20)30831-8.
[55] S. Perlman, A.A. Dandekar, Immunopathogenesis of coronavirus infections:
implications for SARS, Nat. Rev. Immunol. 5 (2005) 917–927, https://doi.org/
10.1038/nri1732.
[56] M.S. Yip, N.H.L. Leung, C.Y. Cheung, P.H. Li, H.H.Y. Lee, M. Da¨
eron, J.S.M. Peiris,
R. Bruzzone, M. Jaume, Antibody-dependent infection of human macrophages by
severe acute respiratory syndrome coronavirus, Virol. J. 11 (2014) 82, https://doi.
org/10.1186/1743-422X-11-82.
[57] L. Liu, Q. Wei, Q. Lin, J. Fang, H. Wang, H. Kwok, H. Tang, K. Nishiura, J. Peng,
Z. Tan, T. Wu, K.-W. Cheung, K.-H. Chan, X. Alvarez, C. Qin, A. Lackner,
S. Perlman, K.-Y. Yuen, Z. Chen, Anti-spike IgG causes severe acute lung injury by
skewing macrophage responses during acute SARS-CoV infection, JCI Insight 4
(2019), https://doi.org/10.1172/jci.insight.123158.
[58] A.M. Arvin, K. Fink, M.A. Schmid, A. Cathcart, R. Spreaco, C. Havenar-Daughton,
A. Lanzavecchia, D. Corti, H.W. Virgin, A perspective on potential antibody-
dependent enhancement of SARS-CoV-2, Nature 584 (2020) 353–363, https://doi.
org/10.1038/s41586-020-2538-8.
[59] W.S. Lee, A.K. Wheatley, S.J. Kent, B.J. DeKosky, Antibody-dependent
enhancement and SARS-CoV-2 vaccines and therapies, Nat. Microbiol. 5 (2020)
1185–1191, https://doi.org/10.1038/s41564-020-00789-5.
[60] J.K. DeMarco, W. Severson, D. DeMarco, G. Pogue, J.D. Gabbard, K.E. Palmer, At
the intersection between SARS-CoV-2, macrophages and the adaptive immune
response: a key role for antibody-dependent pathogenesis but not enhancement of
infection in COVID-19, BioRxiv (2021), https://doi.org/10.1101/
2021.02.22.432407, 2021.02.22.432407.
[61] S. Sridhar, A. Luedtke, E. Langevin, M. Zhu, M. Bonaparte, T. Machabert,
S. Savarino, B. Zambrano, A. Moureau, A. Khromava, Z. Moodie, T. Westling,
C. Mascare˜
nas, C. Frago, M. Cort´
es, D. Chansinghakul, F. Noriega,
A. Bouckenooghe, J. Chen, S.-P. Ng, P.B. Gilbert, S. Gurunathan, C.
A. DiazGranados, Effect of dengue serostatus on dengue vaccine safety and
efcacy, N. Engl. J. Med. 379 (2018) 327–340, https://doi.org/10.1056/
NEJMoa1800820.
[62] P.M. Taylor, B.A. Askonas, Inuenza nucleoprotein-specic cytotoxic T-cell clones
are protective in vivo, Immunology 58 (1986) 417–420.
[63] B.S. Graham, L.A. Bunton, P.F. Wright, D.T. Karzon, Role of T lymphocyte subsets
in the pathogenesis of primary infection and rechallenge with respiratory syncytial
virus in mice, J. Clin. Invest. 88 (1991) 1026–1033, https://doi.org/10.1172/
JCI115362.
[64] J. Zhao, J. Zhao, S. Perlman, T cell responses are required for protection from
clinical disease and for virus clearance in severe acute respiratory syndrome
coronavirus-infected mice, J. Virol. 84 (2010) 9318–9325, https://doi.org/
10.1128/JVI.01049-10.
[65] A. Grifoni, D. Weiskopf, S.I. Ramirez, J. Mateus, J.M. Dan, C.R. Moderbacher, S.
A. Rawlings, A. Sutherland, L. Premkumar, R.S. Jadi, D. Marrama, A.M. de Silva,
A. Frazier, A.F. Carlin, J.A. Greenbaum, B. Peters, F. Krammer, D.M. Smith,
S. Crotty, A. Sette, Targets of t cell responses to SARS-CoV-2 coronavirus in humans
with COVID-19 disease and unexposed individuals, Cell 181 (2020) 1489–1501,
https://doi.org/10.1016/j.cell.2020.05.015, e15.
[66] J. Braun, L. Loyal, M. Frentsch, D. Wendisch, P. Georg, F. Kurth, S. Hippenstiel,
M. Dingeldey, B. Kruse, F. Fauchere, E. Baysal, M. Mangold, L. Henze, R. Lauster,
M.A. Mall, K. Beyer, J. R¨
ohmel, S. Voigt, J. Schmitz, S. Miltenyi, I. Demuth, M.
A. Müller, A. Hocke, M. Witzenrath, N. Suttorp, F. Kern, U. Reimer, H. Wenschuh,
C. Drosten, V.M. Corman, C. Giesecke-Thiel, L.E. Sander, A. Thiel, SARS-CoV-2-
reactive T cells in healthy donors and patients with COVID-19, Nature 587 (2020)
270–274, https://doi.org/10.1038/s41586-020-2598-9.
[67] L. Ni, F. Ye, M.-L. Cheng, Y. Feng, Y.-Q. Deng, H. Zhao, P. Wei, J. Ge, M. Gou, X. Li,
L. Sun, T. Cao, P. Wang, C. Zhou, R. Zhang, P. Liang, H. Guo, X. Wang, C.-F. Qin,
F. Chen, C. Dong, Detection of SARS-CoV-2-Specic humoral and cellular
immunity in COVID-19 convalescent individuals, Immunity 52 (2020) 971–977,
https://doi.org/10.1016/j.immuni.2020.04.023, e3.
[68] D. Weiskopf, K.S. Schmitz, M.P. Raadsen, A. Grifoni, N.M.A. Okba, H. Endeman, J.
P.C. van den Akker, R. Molenkamp, M.P.G. Koopmans, E.C.M. van Gorp, B.
L. Haagmans, R.L. de Swart, A. Sette, R.D. de Vries, Phenotype and kinetics of
SARS-CoV-2-specic T cells in COVID-19 patients with acute respiratory distress
syndrome, Sci. Immunol. 5 (2020), https://doi.org/10.1126/sciimmunol.abd2071.
[69] T. Sekine, A. Perez-Potti, O. Rivera-Ballesteros, K. Strålin, J.-B. Gorin, A. Olsson,
S. Llewellyn-Lacey, H. Kamal, G. Bogdanovic, S. Muschiol, D.J. Wullimann,
T. Kammann, J. Emgård, T. Parrot, E. Folkesson, Karolinska COVID-19 Study
Group, O. Rooyackers, L.I. Eriksson, J.-I. Henter, A. S¨
onnerborg, T. Allander,
J. Albert, M. Nielsen, J. Klingstr¨
om, S. Gredmark-Russ, N.K. Bj¨
orkstr¨
om, J.
K. Sandberg, D.A. Price, H.-G. Ljunggren, S. Aleman, M. Buggert, Robust t cell
immunity in convalescent individuals with asymptomatic or mild COVID-19, Cell
183 (2020) 158–168, https://doi.org/10.1016/j.cell.2020.08.017, e14.
[70] N. Le Bert, A.T. Tan, K. Kunasegaran, C.Y.L. Tham, M. Hafezi, A. Chia, M.H.
Y. Chng, M. Lin, N. Tan, M. Linster, W.N. Chia, M.I.-C. Chen, L.-F. Wang, E.E. Ooi,
S. Kalimuddin, P.A. Tambyah, J.G.-H. Low, Y.-J. Tan, A. Bertoletti, SARS-CoV-2-
specic T cell immunity in cases of COVID-19 and SARS, and uninfected controls,
Nature 584 (2020) 457–462, https://doi.org/10.1038/s41586-020-2550-z.
[71] W.F. Garcia-Beltran, E.C. Lam, K.S. Denis, A.D. Nitido, Z.H. Garcia, B.M. Hauser,
J. Feldman, M.N. Pavlovic, D.J. Gregory, M.C. Poznansky, A. Sigal, A.G. Schmidt,
A.J. Iafrate, V. Naranbhai, A.B. Balazs, Circulating SARS-CoV-2 variants escape
neutralization by vaccine-induced humoral immunity, MedRxiv (2021), https://
doi.org/10.1101/2021.02.14.21251704, 2021.02.14.21251704.
[72] D. Planas, T. Bruel, L. Grzelak, F. Guivel-Benhassine, I. Staropoli, F. Porrot, C.
Planchais, J. Buchrieser, M. M. Rajah, E. Bishop, M. Albert, F. Donati, S. Behillil, V.
Enouf, M. Maquart, M. Gonzalez, J. De S`
eze, H. P´
er´
e, D. Veyer, A. S`
eve, E. Simon
Lori`
ere, S. Fa-Kremer, K. Stec, H. Mouquet, L. Hocqueloux, S. van der Werf, T.
Prazuck, O. Schwartz, Sensitivity of infectious SARS-CoV-2 B.1.1.7 and B.1.351
variants to neutralizing antibodies bioRxiv, (n.d.). https://www.biorxiv.org/con
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 late’ 90, 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