Developing a safe and effective COVID-19 vaccine is
a global priority to end this pandemic. In their doseescalation, single-centre, open-label, phase 1 trial
Published in The Lancet, Feng-Cai Zhu and colleagues1
Report the safety, tolerability, and immunogenicity
Of a recombinant adenovirus type-5 (Ad5) vectored
COVID-19 vaccine, which expresses the full length spike
Glycoprotein of the Wuhan-Hu-1 strain of severe acute
Respiratory syndrome corona virus 2 (SARS-CoV-2).
108 healthy adults who had not been exposed to
SARS-CoV-2, aged between 18 and 60 years (mean
Age 36·3 years, 49% female), were sequentially enrolled
To receive the low, middle, or high dose of the vaccine,
Given as an intramuscular injection, and observed for
And safety.12, 13 these concerns will need to be addressed
In future clinical studies with close monitoring and
Regulatory review. Amid these uncertainties, this report
Of an immunogenic, tolerable vaccine candidate is
Encouraging at the starting line for COVID-19 vaccine
Development. Vaccine candidates shown to be efficacious will require substantial, well directed, and globally
Coordinated investments in production and delivery for
Their benefit to be realized.
Domain because of better immunogenic and protective
Potential, but using different antigen delivery platforms
(eg, recombinant protein or replicating or non-replicating
viral-vector based vaccines and DNA or mRNA vaccines);
Several are entering phase 1 clinical trials, or pending
results.4, 5 looking forward, other than immunogenicity,
Future trial design to establish efficacy will need to define
The target groups (eg, health-care workers, individuals at
High risk of severe illness), clinical endpoints (eg, reduction
In virologically confirmed clinical illness, hospitalizations,
Deaths), optimal duration of observation (eg, virus
Exposure, side-effects, antibody titre change), and to
Anticipate antigenic change over time.
Results of this study indicate that some host
Factors might affect vaccine response. Suboptimal
immunogenicity was reported among older participants,
echoing the challenge seen with influenza vaccination.
Further study in the older age group and the inclusion of
individuals with underlying conditions are important, as
they are at risk of severe disease and might benefit most
from vaccine prevention. Pre-existing immunity against
the Ad5 vector could compromise immunogenicity,
potentially limiting effectiveness in populations in which
the virus is endemic. The reported high seroprevalence
(around 30–80%) in many countries had posed substantial
challenges in vector-based vaccine development for other
infections (eg, Ebola virus, HIV).6–8 Whether using a rarer
serotype or non-human primate adenovirus, adjuvants,
booster or higher dose regimens, or other delivery platforms (eg, replication-defective vaccinia) could achieve
greater degrees of immunogenicity is unknown and
more research is needed.4–6 Another general concern is
the possibility of antibody-dependent enhancement
(eg, non-neutralising antibodies, Fc γ-receptors) and
increased cellular immunopathology (eg, T-helper-2 or
T-helper-17 cell) in individuals who have been vaccinated if they are subsequently infected by a circulating
SARS-CoV-2 strain, as suggested in preclinical studies
of SARS-CoV-1 and Middle East respiratory syndrome
coronavirus vaccines with whole-length spike glycoprotein
(leading to research on a receptor binding domain-focused
vaccine).9–11 Animal studies can be considered to assess
the potential risk of SARS-CoV-2 vaccine candidates.5
Pre-existing, non-spike-specific T-cell responses from
endemic human coronavirus exposure (eg, OC43,
NL63) that cross-react with SARS-CoV-2 could further
add to the complexity in predicting vaccine response
83–97% of participants. The most commonly reported
systemic adverse reactions were fever (50 [46%]), fatigue
(47 [44%]), headache (42 [39%]), and muscle pain
(18 [17%]), which were generally mild to moderate in
severity, although more frequent in the high dose group.
Notably, high pre-existing Ad5 neutralising antibody
titres (>1:200, in 44–56% of participants) were shown to
compromise seroconversion, and attenuate peak T-cell
responses, although vector-related febrile reactions
were less frequent. Older participants (45–60 years) were
found to have significantly lower humoral responses.
This is one of the first-in-human trials of a COVID-19
vaccine candidate showing immunogenicity.
Two key questions are whether responses are sustained
over time and whether they correlate with clinical
protection after exposure to a circulating strain of
SARS-CoV-2. Data from primate models suggest that
measurable neutralising antibodies and specific T-cell
responses could be associated with protection against
virus challenge in vaccination or reinfection studies.2,3
Further research, however, is necessary to evaluate safety,
clinical efficacy, and duration of protection. A phase 2
study of this experimental vaccine (middle or low dose) has
begun in China (NCT04341389) and Canada has approved
an early phase human trial (NCT04398147).Other vaccine
candidates are in rapid development. They are mostly
based on the spike glycoprotein or its receptor binding
28 days. At around 14 days, neutralising antibodies were
detectable with live virus or pseudovirus neutralisation
assays, in addition to binding antibodies (to receptor
binding domain, spike glycoprotein) measured by ELISA.
Dose-dependent antibody responses peaked at 28 days,
with seroconversion (>four-fold increase in neutralising
antibody titre) documented in 50–75% of participants in
the middle and high dose groups. Further, specific T-cell
responses toward the spike glycoprotein were shown
by interferon (IFN) γ enzyme-linked immunospot,
and flow-cytometry (assessing CD4+
and CD8+
, IFNγ,
tumour necrosis factor α, interleukin-2). Dose-dependent responses were detectable starting from 14 days in
