Developing a safe and effective COVID-19 vaccine is

a global priority to end this pandemic. In their dose escalation, single-center, 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