Articles

An observer-blind, randomised, placebo-controlled, phase 1,

single ascending dose study of dengue monoclonal antibody
in healthy adults in Australia
Bhagwat Gunale, Nicholas Farinola, Chandrashekhar D Kamat, Cyrus S Poonawalla, Sambhaji S Pisal, Rajeev M Dhere, Claire Miller,
Prasad S Kulkarni

Summary
Background Dengue is highly prevalent in Asia and Latin America and has no specific dengue antiviral treatment. A Lancet Infect Dis 2024
recombinant monoclonal antibody (VIS513) that neutralises all four serotypes of the dengue virus has been developed Published Online
in India. After confirmation of safety and efficacy in preclinical studies, it was tested in a first-in-human study to February 23, 2024
https://doi.org/10.1016/
assess the safety and pharmacokinetics.
S1473-3099(24)00030-6
See Online/Comment
Methods This was a partially blind (observer-blind), randomised, placebo-controlled, phase 1, single ascending dose https://doi.org/10.1016/
study in Australia. Participants were dengue naive, healthy adults (aged 18–45 years) with no clinically significant S1473-3099(24)00083-5
disorders or immunosuppressive conditions. Four dose levels of dengue monoclonal antibody (ie, 1 mg/kg, 3 mg/kg, Serum Institute of India, Pune,
7 mg/kg, and 12 mg/kg; n=4 for 1 mg/kg and n=10 each for 3 mg/kg, 7 mg/kg, and 12 mg/kg doses) were assessed in India (B Gunale MD,
a dose-ascending way with a placebo control (n=2 for each dose cohort, total n=6) for each cohort except for 1 mg/kg. C D Kamat PhD,
C S Poonawalla DSc,
Within each cohort, participants were first randomly assigned (1:1) in a sentinel sub-cohort and then randomly S S Pisal PhD, R M Dhere PhD,
assigned (9:1) in an expansion sub-cohort to dengue monoclonal antibody or placebo except for the 1 mg/kg cohort. P S Kulkarni MD); CMAX Clinical
Participants, investigators, and outcome assessors were masked and treatment administrators were not masked. Research, Adelaide, SA,
40 participants received a single intravenous injection or infusion of either dengue monoclonal antibody or placebo Australia (N Farinola BMBS);
PPD, Cambridge, UK
over a period of 3 min to 2 h and were followed up until day 85. The primary outcomes were proportion of participants (C Miller BA)
with adverse events and serious adverse events (SAEs) up to 84 days after dosing whereas the secondary outcomes Correspondence to:
were to assess the pharmacokinetic profile of dengue monoclonal antibody and to assess the presence of anti-drug Prasad S Kulkarni, Serum
antibody (ADA) to dengue monoclonal antibody. All participants were included in the safety analysis and the Institute of India, Pune 412307,
pharmacokinetic population involved participants receiving dengue monoclonal antibody. This study is registered India
drpsk@seruminstitute.com
with ClinicalTrials.gov, NCT03883620.

Findings Between March 22 and Dec 23, 2019, 40 healthy adults were randomly assigned and all completed the study.
There were no SAEs reported. None of the placebo recipients (n=6) reported any adverse events. 31 (91%) of 34 participants
receiving dengue monoclonal antibody reported 143 adverse events (1 mg/kg: four [100%] of four participants; 3 mg/kg:
ten [100%] of ten participants; 7 mg/kg: seven [70%] of ten participants; 12 mg/kg: ten [100%] of ten participants). Of
these 143 adverse events, 80 were treatment-related adverse events in 28 (82%) of 34 participants. Headache (16 [47%] of
34), infusion reaction (11 [32%] of 34), lymphopenia (seven [21%] of 34), fatigue (five [15%] of 34), and pyrexia (four [12%]
of 34) were the most common reactions. Infusion reactions were reduced in the 7 mg/kg (two [20%] of ten participants)
and 12 mg/kg (three [30%] of ten) cohorts with paracetamol premedication compared with the 3 mg/kg cohort (five [50%]
of ten). The majority of adverse events were grade 1 or grade 2 in severity, and resolved completely. Median maximum
serum concentrations ranged from 28 μg/mL (1 mg/kg) to 525 μg/mL (12 mg/kg). The median elimination half-life
ranged from 775 h (1 mg/kg) to 878 h (12 mg/kg). No ADA against dengue monoclonal antibody was detected.

Interpretation Dengue monoclonal antibody was safe and well tolerated. It showed a dose-proportionate increase in
pharmacokinetic exposure. These data support further evaluation of dengue monoclonal antibody in patients with
dengue for safety and efficacy.

Funding Serum Institute of India.

Copyright © 2024 Elsevier Ltd. All rights reserved.

Introduction 2019.1 Another study also estimated about 100 million

Dengue is the most common mosquito-borne viral
disease of humans. The WHO regions of the Americas,
South-East Asia, and Western Pacific are the most
seriously affected. Globally, dengue cases have increased
from about 30 million in 1990 to about 56 million in
infections and 40 467 (95% CI 17 620–49 778) deaths due
to dengue in 2017.2
Dengue was responsible for around 500 000 admissions
to hospital for treament3 and about 2∙38 million
disability-adjusted life-years lost in 2019.1 The spread of

www.thelancet.com/infection Published online February 23, 2024 https://doi.org/10.1016/S1473-3099(24)00030-6 1

 Articles
Research in context
Evidence before this study
The majority of antibodies in individuals infected with dengue
virus are against the immunodominant epitopes of envelope
protein and premembrane protein, which could be involved in
antibody-dependent enhancement of dengue. Dengue
monoclonal antibody (earlier known as VIS513) is an
engineered humanised monoclonal antibody that binds to a
non-immunodominant epitope on domain III of envelope
protein (EDIII). Dengue monoclonal antibody has shown
specific neutralisation of all four serotypes of dengue virus in
in-vivo animal models and in-vitro studies. Dengue monoclonal
antibody was safe and no toxicity was observed in preclinical
studies in mice, rats, rabbits, and non-human primates at doses
up to 400 mg/kg. Technology to manufacture dengue
monoclonal antibody was transferred to India. We searched
PubMed for clinical trials published from Jan 1, 2008, to
Aug 19, 2023, with no language restrictions, using the terms
“dengue monoclonal antibody” and “clinical trial”. We found no
clinical trial publications on dengue monoclonal antibody.
This monoclonal antibody is being developed for therapeutic
use in dengue.
dengue is increasing due to factors such as climate
change, globalisation, and viral evolution,4 and is
emerging as a health problem for international
travellers.5,6
There are four distinct dengue virus serotypes (ie,
DENV-1, DENV-2, DENV-3, and DENV-4), with most
endemic countries reporting circulation of all four
serotypes.7 Dengue virus contains three structural
proteins: premembrane, capsid, and envelope (containing
domain I, domain II, and domain III), and seven non-
structural proteins.8 Dengue presentation ranges from
dengue with or without warning signs to severe dengue.7
There is currently no specific treatment for dengue and
preventive measures include mosquito control. Two
vaccines (Dengvaxia, Sanofi Pasteur, France; and Qdenga,
Takeda, Germany) have been licensed in a few countries,
albeit with some limitations. Dengvaxia has shown lower
efficacy for DENV-1 and DENV-2 and is recommended
only in individuals with previous dengue infection.9,10 No
efficacy of Qdenga was observed for DENV-3 in
participants who were seronegative at baseline and there
were too few cases to conclude efficacy against DENV-4.11
Current management of dengue includes supportive
care in the form of fluid replacement and close clinical
monitoring.12 Thus, effective anti-dengue treatments are
an unmet medical need.
Based on structural and non-structural proteins,
antiviral therapeutics against dengue are under develop­
ment.13 The majority of the naturally acquired dengue
antibodies are against the immunodominant epitopes of
the envelope protein fusion loop and the premembrane
proteins that provide long-term immunity against
2 www.thelancet.com/infection Published online February 23, 2024 https://doi.org/10.1016/S1473-3099(24)00030-6
Added value of this study
This is the first worldwide report on the safety and
pharmacokinetics of dengue monoclonal antibody in healthy
adults. Almost all adverse events were mild to moderate and
resolved completely. Slowing the rate of infusion and
premedication with 1 g oral paracetamol about 30 min before
the start of infusion abrogated infusion-related reactions such
as fever, chills, and rigors. Dengue monoclonal antibody was
found to be safe and well tolerated with no serious safety
concerns reported. Dengue monoclonal antibody showed a
dose-dependent increase in pharmacokinetic exposure without
any anti-drug antibody response.
Implications of all the available evidence
There is no therapeutic approved for the treatment of dengue.
Current treatment includes maintenance of hydration and
symptomatic treatment. The safety of dengue monoclonal
antibody in healthy adults, as shown by this study, will now
pave the way forward for evaluation of its efficacy and safety in
a phase 2 study in patients with dengue.
homotypic dengue virus infection but only short-term
immunity against heterotypic dengue virus infec­ tion.
After waning, these antibodies can be involved in
antibody-dependent enhancement (ADE) with hetero­
typic dengue virus infection.14,15 Therefore, therapeutic
monoclonal anti­ bodies for dengue should be able to
neutralise all four dengue virus serotypes. Dengue
monoclonal antibody (VIS513) is an engineered
humanised monoclonal antibody that binds to a non-
immunodominant epitope on domain III of the envelope
protein (EDIII) and has shown potent, specific neutra­
lisation of all four serotypes of dengue virus.16 The
antibody has shown activity in multiple in-vivo models of
dengue infection.16–18 The antibody was shown to
overcome ADE both in vitro and in vivo with minimal, if
any, enhancement of in-vitro infectivity.18 Dengue
monoclonal antibody is a therapeutic and is not intended
for prophylactic use, and the antibody titres will wane
during the umbrella of protection provided by the host
response to the treated infection.
Dengue monoclonal antibody is produced by
recombinant DNA technology in a mammalian cell (ie,
Chinese hamster ovary) line in the USA. After a
technology transfer, the manufacturing and formulation
was optimised in India. Animal toxicity studies did not
show any toxicity. After this evidence, we conducted the
first-in-human study in healthy adults in Australia.
The primary objective was to assess the safety and
tolerability of dengue monoclonal antibody, whereas
the secondary objectives were to assess pharmacokinetic
parameters and anti-drug antibodies (ADAs) to dengue
monoclonal antibody.

Study group
Cohort one (initial safety cohort) Dengue monoclonal antibody
Cohort two Dengue monoclonal antibody; placebo
Cohort three Dengue monoclonal antibody; placebo
Cohort four Dengue monoclonal antibody; placebo
Table 1: Treatment allocation
Methods
Study design and participants
This was a partially blind (observer-blind), randomised,
placebo-controlled, phase 1, single ascending dose trial in
healthy adults. The study was conducted at CMAX
Clinical Research, which is a dedicated phase 1 clinical
research unit based in Adelaide, SA, Australia. This
facility was contracted by Serum Institute of India (Pune,
India) for the conduct of this study. The study was
conducted from March to December, 2019, and was
approved by Bellberry Human Research Ethics
Committee. The study followed the Good Clinical
Practice Guidelines, Declaration of Helsinki, and the
Australian National Statement on Ethical Conduct in
Human Research.
Healthy adults (aged 18–45 years) with negative dengue
NS1 and dengue IgG antibodies who provided written
consent were included in the study. Presence of fever or
acute infection, clinically significant disorders, and
allergic reactions to the study product were exclusion
criteria (appendix pp 73–75).
Randomisation and masking
There were five cohorts with doses of 1 mg/kg (n=4),
3 mg/kg (n=12), 7 mg/kg (n=12), 12 mg/kg (n=12), and
25 mg/kg (n=12) of dengue monoclonal antibody
(table 1). In cohort one, four participants were
administered 1 mg/kg dengue monoclonal antibody
sequentially. For each of the other four cohorts, there
were two sub-cohorts: a sentinel cohort (n=2) and an
expansion cohort (n=10). In sentinel sub-cohorts,
participants were randomly assigned (1:1) to dengue
monoclonal antibody or placebo. In the expansion sub-
cohorts, the remaining ten participants were randomly
assigned (9:1) to dengue monoclonal antibody or placebo
(table 1). Unequal allocation to dengue monoclonal
antibody and placebo ensured generation of safety data
on dengue monoclonal antibody in more participants.
A computer-generated randomisation schedule pre­
pared by an independent team was provided to the
unmasked pharmacist at Royal Adelaide Hospital (RAH)
Pharmacy (Adelaide, SA, Australia) who had no further
involvement in the trial. Study drugs were dispensed by
the unmasked pharmacist to CMAX Clinical Research.
This was a partially blind (observer-blind) study. In
cohort one, masking was not applicable because there
was no control group, which meant that all participants
were to receive dengue monoclonal antibody. For cohorts
www.thelancet.com/infection Published online February 23, 2024 https://doi.org/10.1016/S1473-3099(24)00030-6
Articles
Dose Number of participants Allocation ratio
1 mg/kg 4 Not applicable
3 mg/kg; 3 mg/kg 10; 2 1:1 for sentinel cohort (n=2) and 9:1 for expansion cohort (n=10)
7 mg/kg; 7 mg/kg 10; 2 1:1 for sentinel cohort (n=2) and 9:1 for expansion cohort (n=10)
12 mg/kg; 12 mg/kg 10; 2 1:1 for sentinel cohort (n=2) and 9:1 for expansion cohort (n=10)
two to four, the participants, investigator, and outcome
assessors were masked. The laboratories analysing the
samples were also masked.
RAH Pharmacy staff prepared the study products
(dengue monoclonal antibody or placebo for respective
cohorts) which were transferred to CMAX Clinical
Research in black plastic bags to maintain masking. The
infusion bag was kept at ambient temperature (ie,
below 25°C) for about 20–30 min before dosing.
Procedures
Dengue monoclonal antibody (manufactured by Serum
Institute of India [SIIPL], Pune, India) is a sterile, slightly
yellowish, clear liquid packaged into clear glass vials of
30 mL. Each vial contains dengue monoclonal antibody
25 mg/mL and excipients (batch 3148T0010Z, manu­
facturing date June, 2018).
The placebo (manufactured by SIIPL) was a formulation
buffer containing all the same ingredients as dengue
monoclonal antibody except for the active ingredient
(batch 3228T0010Z, manufacturing date June, 2018). See Online for appendix
Study products were stored between 2°C and 8°C.
40 participants across five cohorts were dosed with
dengue monoclonal antibody or placebo and were
followed up until day 85. Dose escalations occurred after
review of safety data after 7 days by the Protocol Safety
Review Team comprising the principal investigator,
sponsor physicians, and a statistician. Dengue mono­
clonal antibody doses evaluated in the study were selected
on the basis of safety in preclinical studies at doses
ranging from 3 mg/kg to 400 mg/kg. An initial dose of
1 mg/kg was selected to assess any dose-independent
effect of dengue monoclonal antibody. The cohort for the
25 mg/kg dose, cohort five, was not enrolled for safety
reasons because the 12 mg/kg dose caused more adverse
events than a lower dose, although almost all adverse
events were mild to moderate in severity.
Volunteers were screened for up to 28 days before
being randomly assigned on day 1. The eligible
participants were admitted to CMAX Clinical Research a
day before randomisation until day 5 (ie, 96 h after
administration of study drug). On day 1, a single dose
of dengue monoclonal antibody or placebo was
administered as an intravenous injection or infusion
(table 1).
After discharge on day 5, participants visited CMAX six
times over a period of 84 days (days 6, 8, 15, 29, 57,
and 85).
3
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125 participants screened for eligibility
85 excluded
51 inclusion criteria not met
or exclusion criteria met
20 withdrawal by
participant
4 lost to follow-up
4 additional participants
screened
2 withdrawal by
investigator
4 out of screening window
40 participants randomly assigned
34 assigned to dengue monoclonal 6 assigned to placebo
antibody
34 included in safety population 6 included in safety population
34 included in pharmacokinetic
population
34 completed study 6 completed study
Figure: Participant flowchart
Safety was monitored by assessment of vital signs,
physical examination, laboratory testing (haematology
and chemistry), and electrocardiograms (ECGs) at
periodic intervals (appendix pp 55–57).
For cohort one, dengue monoclonal antibody doses
were administered as a slow intravenous injection without
dilution in up to 3 min. For cohorts two to four, dengue
monoclonal antibody or placebo were given by intravenous
infusion using an infusion bag and intravenous line. The
total volume of study products was a calculated dose based
on bodyweight plus priming volume in intravenous line
of 23 mL. The study product was then transferred into an
empty infusion bag and was connected to an infusion
pump. The total dose was administered over a period of
10–30 min for cohort two, 1 h for cohort three, and 1–2 h
for cohort four. The dose calculation and administration
for placebo was followed in the same manner as that for
the respective dengue monoclonal antibody cohort.
Both before and after the administration of study
products, 5 mL of formulation buffer (same as placebo)
was administered to all participants. This formulation
buffer was administered to ensure that intravenous access
was patent before infusion and to ensure that no drug
remained in the cannula after infusion of the study drug.
All participants in cohort three and cohort four were
administered 1 g of paracetamol orally as premedication
about 30 min before dosing to minimise infusion
reactions.
4 www.thelancet.com/infection Published online February 23, 2024 https://doi.org/10.1016/S1473-3099(24)00030-6
The safety assessments included any hypersensitivity
reactions including infusion reactions within 4 h of
infusion, adverse events and serious adverse events
(SAEs) throughout the study period of 84 days, clinical
chemistry and haematology (baseline, day 2, day 5, day 8,
and day 29) and ADAs against dengue monoclonal
antibody (baseline, day 29, and day 85). Severity of
adverse events was rated according to the Division of
AIDS Toxicity Grading criteria.
Clinical chemistry, haematology, and baseline dengue
(ie, NS1 antigen, IgM, and IgG using Bioline Dengue
Duo kit, Abbott, Santa Clara, CA, USA) testing was done
at Australian Clinical Labs, Adelaide (SA, Australia).
A quasi-quantitative validated ELISA method was used
for the measurement of ADAs against dengue
monoclonal antibody in sera samples. The lower limit of
detection (LLOD) for this assay was 133∙57 ng/mL for the
screening assay and 64∙91 ng/mL for the confirmatory
assay.
Samples for pharmacokinetics were collected at
baseline, 5 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h,
72 h, 96 h, 120 h, day 8, day 15, day 29, day 57, and
day 85. Dengue monoclonal antibody concentration in
sera samples was measured using a validated
colorimetric ELISA, in which high-binding microtitre
plates were coated with murine anti-dengue monoclonal
antibody (capture antibody) to capture dengue mono­
clonal antibody in the sera samples. The LLOD was
40 ng/mL and the range of the assay was 40–1600 ng/mL
(appendix p 2).
Pharmacokinetic and ADA sample analysis was
conducted at Syngene International (Benguluru, India).
Outcomes
The primary outcomes were proportion of participants
with adverse events, SAEs, discontinuations due to
adverse events, post-infusion adverse events within 4 h of
dosing, and clinically significant abnormal safety
laboratory findings. The secondary outcomes were the
pharmacokinetic profile of dengue monoclonal antibody
(maximum measured serum concentration over the time
span specified [Cmax], time of the maximum measured
serum concentration [Tmax], the area under the serum
concentration versus time curve [AUC] from time 0 to
the last measurable concentration [AUC0–last], the AUC
extrapolated to infinity (AUC0–∞), elimination or terminal
half-life [t1/2], volume of distribution [Vd], clearance, and
apparent first-order elimination rate constant [kel]) and
the development of any ADA to dengue monoclonal
antibody.
Statistical analysis
Being a phase 1 trial, the study was not powered. It was
planned to have at least ten participants in each dose
group of dengue monoclonal antibody and the placebo
controls for each cohort were pooled together as a control
group (table 1). However, cohort five was not enrolled,
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Placebo Dengue Dengue Dengue Dengue Dengue Overall

(n=6) monoclonal monoclonal monoclonal monoclonal monoclonal (n=40)
antibody antibody antibody antibody antibody
1 mg/kg (n=4) 3 mg/kg (n=10) 7 mg/kg (n=10) 12 mg/kg (n=10) total (n=34)
Age (years) 28·3 (8·5) 27·5 (6·0) 28·0 (5·6) 31·7 (7·7) 24·6 (6·4) 28·0 (6·9) 28·1 (7·0)
Sex*
Male 6 (100%) 2 (50%) 9 (90%) 9 (90%) 10 (100%) 30 (88%) 36 (90%)
Female 0 2 (50%) 1 (10%) 1 (10%) 0 4 (12%) 4 (10%)
Race
Asian 0 0 2 (20%) 0 1 (10%) 3 (9%) 3 (8%)
Black or African American 0 0 0 1 (10%) 0 1 (3%) 1 (2%)
White 6 (100%) 4 (100%) 8 (80%) 9 (90%) 9 (90%) 30 (88%) 36 (90%)
Ethnicity
Hispanic or Latino 1 (17%) 0 0 0 1 (10%) 1 (3%) 2 (5%)
Not Hispanic or Latino 5 (83%) 3 (75%) 9 (90%) 10 (100%) 9 (90%) 31 (91%) 36 (90%)
Unknown 0 1 (25%) 1 (10%) 0 0 2 (6%) 2 (5%)
Height (cm) 177·8 (9·8) 172·0 (13·0) 177·1 (8·0) 179·5 (9·1) 177·8 (6·3) 177·4 (8·4) 177·5 (8·5)
Height range (cm) 163·0–191·0 160·0–186·0 162·0–186·0 164·0–189·0 168·0–187·0 160·0–189·0 160·0–191·0
Weight (kg) 78·6 (14·5) 70·8 (11·4) 77·5 (11·2) 78·5 (11·9) 77·0 (10·1) 76·9 (10·9) 77·1 (11·3)
Weight range (kg) 61·1–96·2 59·7–85·1 63·7–94·8 62·3–96·8 58·7–93·4 58·7–96·8 58·7–96·8
BMI (kg/m2) 24·75 (3·29) 23·85 (2·16) 24·76 (3·52) 24·33 (3·03) 24·28 (2·18) 24·39 (2·77) 24·44 (2·81)

Data are mean (SD) or n (%), unless otherwise stated. *Self-reported by participants, with the option of male or female.

Table 2: Baseline demographics and other parameters

as mentioned previously. All analyses were done
descriptively.
For categorical variables, frequencies and percentages
were presented. Continuous variables were summarised
using descriptive statistics (mean, SD, minimum, and
maximum).
Safety data were analysed by group as total number of
adverse events and participants with at least one adverse
event (n and percentage).
Dengue monoclonal antibody concentration data were
summarised using descriptive statistics (n, geometric
mean, median, minimum, and maximum) by sampling
timepoint and dose. Non-compartmental analysis was
used to calculate the pharmacokinetic parameters of
dengue monoclonal antibody. This analysis was done
using Phoenix WinNonlin version 8.0 (Pharsight,
St Louis, MO, USA).
The ADA response was defined as a participant with a
baseline negative ADA status converting to a positive
ADA status after study drug administration or a two-fold
rise in ADA titres after study drug administration in
participants who had baseline ADA-positive status.
The safety population included all participants who
were enrolled and received a study drug. The safety
population was used in the safety analyses. The
pharmacokinetic population included participants who
received dengue monoclonal antibody and had
concentration data available.
All statistical analyses were conducted using SAS
version 9.4; see appendix for details (pp 133–62). The trial
is registered with ClinicalTrials.gov, NCT03883620.
Role of the funding source
The funder of the study was involved in study design,
data interpretation, and writing of the report, but was not
involved in data collection and data analysis. All the
authors had full access to the data.
Results
The study was conducted from March 22 to Dec 23, 2019.
125 participants were screened for eligibility, of whom
40 (32%) were randomly assigned. All participants
completed the study follow-up (figure).
40 participants were part of the safety population and
34 participants were part of the pharmacokinetic
population (figure).
Most of the participants were White (n=36, 90%) and
male (n=36, 90%). The mean age was 28∙1 years (SD 7∙0)
and mean weight was 77∙1 kg (11∙3; table 2). All
40 participants were negative for ADA at baseline.
Only two major protocol deviations were reported: one
participant missed day 6 and day 15 visits and one
participant’s day 5 haematology tests could not be
conducted owing to sample collection in a wrong container.
24 participants had at least one minor protocol deviation.
These deviations were mostly related to procedures done
outside of the protocol-allowed window by a few minutes
for most of the participants (appendix pp 5–7), which were
not expected to have substantial effects on the study
outcomes, as based on clinical judgement of the
investigator and sponsor medical officers.
There were no SAEs in the study and no adverse events
that led to study withdrawal. No adverse events were

www.thelancet.com/infection Published online February 23, 2024 https://doi.org/10.1016/S1473-3099(24)00030-6 5

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Placebo Dengue Dengue Dengue Dengue Dengue Overall (n=40)

(n=6) monoclonal monoclonal monoclonal monoclonal monoclonal
antibody 1 mg/kg antibody 3 mg/kg antibody antibody antibody
(n=4) (n=10) 7 mg/kg (n=10) 12 mg/kg (n=10) total (n=34)
Any adverse event 0 4 (100%); 15 10 (100%); 50 7 (70%); 23 10 (100%); 55 31 (91%); 143 31 (78%); 143
Any treatment-related 0 4 (100%); 8 10 (100%); 31 4 (40%); 9 10 (100%); 32 28 (82%); 80 28 (70%); 80
adverse event
Any adverse event of grade 3 0 0 0 1 (10%); 1 5 (50%); 5 6 (18%); 6 6 (15%); 6
or 4
Any treatment-related 0 0 0 1 (10%); 1 5 (50%); 5 6 (18%); 6 6 (15%); 6
adverse event of grade 3 or 4
Any serious adverse event 0 0 0 0 0 0 0
Adverse events within 4 h of start of dosing
Any adverse event 0 3 (75%); 3 9 (90%); 17 2 (20%); 2 4 (40%); 8 18 (53%); 30 18 (45%); 30
Any treatment-related 0 3 (75%); 3 9 (90%); 17 2 (20%); 2 4 (40%); 8 18 (53%); 30 18 (45%); 30
adverse event
Any adverse event of 0 0 0 0 0 0 0
grade 3 or 4

Data are number of participants with an adverse event (proportion of total participants, %); total number of adverse events.

Table 3: Overall summary of adverse events

reported in the placebo group (n=6). In the dengue
monoclonal antibody groups, 31 (91%) of 34 participants
who received dengue monoclonal antibody reported at
least one adverse event and a total of 143 adverse events
were reported. Of these 143 adverse events, 15 occurred
in four (100%) of four participants in cohort one,
50 occurred in ten (100%) of ten participants in cohort
two, 23 occurred in seven (70%) of ten participants in
cohort three, and 55 occurred in ten (100%) of ten
participants in cohort four. Among these 143 adverse
events, 80 were treatment-related in 28 (82%) of
34 participants. Of these 80 treatment-related adverse
events, 30 were within 4 h of infusion in 18 (53%) of
34 participants (table 3).
The distribution of treatment-related adverse events
within 4 h of infusion was three events in three (75%) of
four participants in cohort one; 17 events in nine (90%)
of ten participants in cohort two; two events in two (20%)
of ten participants in cohort three; and eight events in
four (40%) of ten participants in cohort four. All 30 events
were grade 1 or grade 2 in severity (table 3). These were
headache, dizziness, lethargy, tremor, infusion reaction,
fatigue, catheter site pruritus, tachycardia, nausea and
vomiting, neck pain, and peripheral coldness.
The distribution of 80 treatment-related adverse events
was eight events in four (100%) of four participants in
cohort one; 31 events in ten (100%) of ten participants in
cohort two; nine events in four (40%) of ten participants
in cohort three; and 32 events in ten (100%) of ten
participants in cohort four. The treatment-related adverse
events were headache, infusion-related reaction, lympho­
penia, fatigue, pyrexia, nausea, tachycardia, lethargy,
myalgia, back pain, decreased appetite, neck pain,
dizziness, postural orthostatic tachycardia syndrome,
presyncope, syncope, tremor, catheter site pruritus,
orchitis, thrombocytopenia, cough, catarrh, tachyphrenia,
abdominal discomfort, abdominal pain, diarrhoea and
bowel movement irregularity, increased aspartate
aminotransferase, increased alanine amino­ transferase,
increased γ-glutamyltransferase, dry eye, and peripheral
coldness (table 4). Presyncope (grade 1; occurring 7∙8 h
after the start of infusion and resolving in 1∙2 h) and
syncope (grade 3; occurring 5∙8 h after the start of
infusion and resolving in 30 min) were reported in
cohort four.
The symptoms of infusion reactions included fever,
chills, rigors, nausea, vomiting, body ache, headache,
increase in blood pressure, tachycardia, and fatigue
during infusion or within the first 24 h after the start of
infusion. Frequency of infusion reactions was one event
in one (25%) of four participants in cohort one; seven
events in five (50%) of ten participants in cohort two;
three events in two (20%) of ten participants in cohort
three; and three events in three (30%) of ten participants
in cohort four (table 4). These reactions were of grade 1 or
grade 2 severity, were transient, and resolved without any
sequelae.
Median time to onset of adverse events within 7 days of
administration of dengue monoclonal antibody was
5∙9 h (range 0·1–149·3) across the four dose groups.
Median time to onset of infusion reactions was 2∙5 h
(0∙5–10∙5) across the four dose groups and that for
lymphopenia was about 25∙0 h (24∙6–26∙2).
Median duration of adverse events was 11∙8 h
(range 0–2511∙0) for adverse events within 7 days of
administration of dengue monoclonal antibody across
dose groups. Median duration of infusion reactions was
31∙9 h (31·9–31·9) in cohort one, 7∙6 h (0∙6–43∙0) in
cohort two, 2∙5 h (0∙1–9∙3) in cohort three, and 11∙8 h
(6∙2–18∙1) in cohort four. The median duration of

6 www.thelancet.com/infection Published online February 23, 2024 https://doi.org/10.1016/S1473-3099(24)00030-6

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Dengue monoclonal Dengue monoclonal Dengue monoclonal Dengue monoclonal Dengue

antibody 1 mg/kg antibody 3 mg/kg antibody 7 mg/kg antibody 12 mg/kg monoclonal
(n=4) (n=10) (n=10) (n=10) antibody total
(n=34)
Any treatment-related adverse event 4 (100%); 8 10 (100%); 31 4 (40%); 9 10 (100%); 32 28 (82%); 80
Headache 2 (50%); 2 5 (50%); 5 1 (10%); 1 7 (70%); 8 15 (44%); 16
Infusion-related reaction 1 (25%); 1 5 (50%); 7 2 (20%); 3 3 (30%); 3 11 (32%); 14
Lymphopenia 0 1 (10%); 1 1 (10%); 1 5 (50%); 5 7 (21%); 7
Fatigue 0 3 (30%); 3 0 1 (10%); 1 4 (12%); 4
Pyrexia 0 1 (10%); 1 0 3 (30%); 3 4 (12%); 4
Nausea 0 2 (20%); 2 0 1 (10%); 1 3 (9%); 3
Tachycardia 0 0 0 2 (20%); 2 2 (6%); 2
Lethargy 1 (25%); 1 1 (10%); 1 0 0 2 (6%); 2
Myalgia 0 1 (10%); 1 1 (10%); 1 0 2 (6%); 2
Back pain 0 1 (10%); 1 0 1 (10%); 1 2 (6%); 2
Decreased appetite 0 2 (20%); 2 0 0 2 (6%); 2
Vomiting 0 1 (10%); 1 0 0 1 (3%); 1
Neck pain 0 1 (10%); 1 0 0 1 (3%); 1
Dizziness 0 0 1 (10%); 1 0 1 (3%); 1
Postural orthostatic tachycardia syndrome 0 1 (10%); 1 0 0 1 (3%); 1
Presyncope 0 0 0 1 (10%); 1 1 (3%); 1
Syncope 0 0 0 1 (10%); 1 1 (3%); 1
Tremor 0 0 0 1 (10%); 1 1 (3%); 1
Catheter site pruritus 0 1 (10%); 1 0 0 1 (3%); 1
Orchitis 0 0 0 1 (10%); 1 1 (3%); 1
Thrombocytopenia 0 0 0 1 (10%); 1 1 (3%); 1
Cough 0 0 0 1 (10%); 1 1 (3%); 1
Catarrh 0 0 0 1 (10%); 1 1 (3%); 1
Tachyphrenia 0 1 (10%); 1 0 0 1 (3%); 1
Abdominal discomfort 1 (25%); 1 0 0 0 1 (3%); 1
Abdominal pain 1 (25%); 1 0 0 0 1 (3%); 1
Diarrhoea 1 (25%); 1 0 0 0 1 (3%); 1
Bowel movement irregularity 1 (25%); 1 0 0 0 1 (3%); 1
Increased aspartate aminotransferase 0 1 (10%); 1 0 0 1 (3%); 1
Increased alanine aminotransferase 0 0 1 (10%); 1 0 1 (3%); 1
Increased γ-glutamyltransferase 0 0 1 (10%); 1 0 1 (3%); 1
Dry eye 0 0 0 1 (10%); 1 1 (3%); 1
Peripheral coldness 0 1 (10%); 1 0 0 1 (3%); 1

Data are number of participants with an adverse event (proportion of total participants, %); total number of adverse events.

Table 4: Treatment-related adverse events by preferred term

lymphopenia across dose groups was about 72∙0 h
(71∙9–1323∙3).
The majority of adverse events were grade 1 (122 events
in 16 [47%] of 34 participants) and grade 2 (15 events in
nine (27%) of 34 participants) in severity. Four adverse
events in four (12%) of 34 participants were grade 3 in
severity and two adverse events in two (6%) of
34 participants were grade 4 in severity. All grade 3
adverse events were reported in cohort four and were
syncope (n=1), orchitis (n=1), and lymphopenia (n=2).
Orchitis occurred about 28 days after infusion and was
associated with pain and inflammation in the scrotal
area. For one participant from cohort four, baseline
absolute lymphocyte count (ALC) was 1∙5 × 10⁹ per L
(normal). For this participant, ALC was 0∙4 × 10⁹ per L
(grade 3) on day 2 (at 24 h after dosing), and 0∙6 × 10⁹
per L (grade 1) on day 8 and day 29. For another
participant from cohort four, baseline ALC was 1∙1 × 10⁹
per L (normal). The post-treatment values for this
participant were 0∙4 × 10⁹ per L (grade 3) on day 2,
0∙5 × 10⁹ per L (grade 2) on day 5, 0∙5 × 10⁹ per L (grade 2)
on day 8, 0∙4 × 10⁹ per L (grade 3) on day 29, and 0∙6 × 10⁹
per L (grade 1) at last visit (6 weeks later). Neither of these
participants developed any symptoms.
Two events of lymphopenia were grade 4 in severity
(one participant from cohort three and one from

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cohort four). For the participant from cohort three,
baseline and day 2 ALC were 1∙4 × 10⁹ per L (normal) and
0∙3 × 10⁹ per L (grade 4), respectively, which rose to
0∙6 × 10⁹ per L (grade 1) on day 8 and day 29. For the
participant from cohort four, baseline and day 2 ALC
were 1∙4 × 10⁹ per L (normal) and 0∙3 × 10⁹ per L (grade 4),
respectively, and 0∙7 × 10⁹ per L (normal), 0∙6 × 10⁹ per L
(grade 1), and 0∙9 × 10⁹ per L (normal) on day 5, day 8,
and day 29, respectively.
136 (95%) of 143 adverse events were completely
resolved. Seven (5%) adverse events in five participants
were either not resolved or were resolving at the last visit.
Of these seven adverse events, four were treatment-
related—three events of lymphopenia and one of orchitis.
At the last follow-up visit, all participants with
lymphopenias were without any symptoms and they
were grade 1 (ie, ALC ≥0∙6 × 10⁹ per L). Of the seven
ongoing adverse events, three unrelated adverse events
included an upper respiratory tract infection in one
participant, and rotator cuff syndrome and fatigue in
another participant.
There were no clinically significant changes in
haematology, clinical chemistry, and urinalysis para­
meters except for seven participants with lymphopenia
and one participant with thrombocytopenia. Lympho­
penia was seen in five participants from cohort four and
one each in cohort two and cohort three. Of these
participants, three had grade 2 lymphopenia, two had
grade 3 lymphopenia, and two had grade 4 lymphopenia.
However, this decrease in lymphocytes was not associated
with any clinical symptoms. Concentrations of
lymphocytes showed a rise on day 5 in all participants
with lymphopenia.
No clinically significant changes in blood pressure,
pulse rate, respiratory rate, and tympanic temperature
were observed except for those changes related to
infusion reactions, tachycardia, and increased blood
pressure in a few participants, which were transient.
No clinically significant changes were detected on ECG
conducted post-infusion compared with baseline, except
for three participants who had increased heart rate due to
infusion. One participant from cohort two had postural
orthostatic tachycardia syndrome that occurred about
7∙5 h after the end of infusion and resolved within 4∙5 h.
Two participants from cohort four had tachycardia. One
of these participants had tachycardia that occurred about
2∙0 h after the end of infusion and resolved in about
6∙0 h. The other participant had tachycardia that occurred
about 5∙0 h after the end of infusion and resolved in
about 1∙0 h. These changes did not require any
intervention and resolved completely. These events were
mild and related to the study drug.
There was a dose-proportionate increase in the Cmax
(28 μg/mL, 91 μg/mL, 210 μg/mL, and 525 μg/mL for the
four dose groups, respectively), the median AUC0–last
(12 000 h*μg/mL, 38 400 h*μg/mL, 104 000 h*μg/mL,
and 168 000 h*μg/mL for the four dose groups,
8 www.thelancet.com/infection Published online February 23, 2024 https://doi.org/10.1016/S1473-3099(24)00030-6
respectively) and the median AUC0–∞ (13 700 h*μg/mL,
47 000 h*μg/mL, 127 000 h*μg/mL, and 207 000 h*μg/mL
for the four dose groups, respectively). Tmax values were
variable across the four dose groups: 0∙13 h (1 mg/kg
dose), 0∙59 h (3 mg/kg dose), 5∙06 h (7 mg/kg dose), and
2∙25 h (12 mg/kg dose). The half-life (t1/2) was similar
across dose groups: 775 h (1 mg/kg dose), 877 h (3 mg/kg
dose), 830 h (7 mg/kg dose), and 878 h (12 mg/kg dose).
Vd, clearance, and kel were also similar across all dose
groups (table 5).
Except for one participant, all participants had dengue
monoclonal antibody concentration below the LLOD (ie,
below 40 ng/mL) before infusion of dengue monoclonal
antibody. This participant had a baseline dengue
monoclonal antibody concentration of 69∙6 μg/mL, a
Cmax of 382 μg/mL, a Tmax of 2∙5 h, and an AUC0–last
127 000 h*μg/mL that was similar to all other participants.
Pharmacokinetic analysis did not show any difference
when this participant was excluded or included in the
analysis of dose proportionality in terms of Cmax, and
AUC0–last, and dose independence in terms of clearance
(appendix pp 9–11).
None of the participants developed ADA response.
Discussion
To our knowledge, this was the first-in-human randomised,
partially blind (observer-blind), placebo-controlled, single
ascending dose study of dengue monoclonal antibody in
healthy adults. Dengue monoclonal antibody administered
at doses ranging from 1 mg/kg to 12 mg/kg as an
intravenous injection or infusion was safe and well
tolerated. Dengue monoclonal antibody also showed dose-
proportionate pharmaco­ kinetic exposure. Headache,
infusion reaction, lympho­penia, fatigue, and pyrexia were
the most common adverse reactions. Almost all adverse
events were of grade 1 or grade 2 severity, and resolved
completely. No deaths, SAEs, or adverse events causing
premature discontinuation were observed.
Most of the adverse events within 4 h of dosing were
related to the infusion and included headache,
dizziness, lethargy, tremor, infusion reaction, fatigue,
catheter site pruritus, tachycardia, nausea, vomiting,
neck pain, and peripheral coldness. One of the known
adverse reactions with approved monoclonal antibodies
is the infusion reactions. Infusion reactions can cause
chills, fever, mild hypotension, dyspnoea, and rash.
Rarely, severe reactions could cause severe hypotension,
anaphylaxis, and cardiac dysfunction. An infusion
reaction usually starts within 30–120 min after the start
of administration of the monoclonal antibody, but
delayed infusion reactions at up to 24 h can occur.
When the monoclonal antibodies bind to the target cell,
cytokines are released into the circulation that cause
the typical symptoms.19
With administration of paracetamol 1 g as pre­
medication in cohorts three and four, these adverse events
were substantially reduced compared with cohort two.
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Dengue monoclonal Dengue monoclonal Dengue monoclonal Dengue monoclonal

antibody 1 mg/kg (n=4) antibody 3 mg/kg (n=10) antibody 7 mg/kg (n=10) antibody 12 mg/kg (n=10)
Cmax (μg/mL)
Geometric mean 26·0 94·8 205 509
Median 28·0 91·1 210 525
Range 16·4–35·5 72·7–139·0 151·0–236·0 382·0–666·0
Tmax (h)
Median 0·13 0·59 5·06 2·25
Range 0·13–1·05 0·25–2·50 1·08–9·27 1·08–9·50
AUC0–last (h*μg/mL)
Geometric mean 12 500 38 600 99 300 168 000
Median 12 000 38 400 104 000 168 000
Range 8290–21 000 28 600–57 000 68 000–130 000 145 000–194 000
AUC0–∞ (h*μg/mL)
Geometric mean 15 400 47 200 121 000 208 000
Median 13 700 47 000 127 000 207 000
Range 10 800–28 000 32 700–67 700 79 000–189 000 171 000–245 000
kel (/h)
Geometric mean 0·000854 0·000799 0·000840 0·000833
Median 0·000899 0·000793 0·000835 0·000791
Range 0·000628–0·00105 0·000536–0·00102 0·000540–0·00119 0·000614–0·00126
t1/2 (h)
Geometric mean 812 867 825 832
Median 775 877 830 878
Range 658–1100 682–1290 582–1280 551–1130
Clearance (mL/h)
Geometric mean 4·55 4·88 4·49 4·41
Median 5·41 4·73 4·55 4·30
Range 2·28–6·88 3·40–6·42 2·31–8·57 3·84–5·10
Vd (mL)
Geometric mean 5250 5490 5030 5020
Median 5120 5580 5010 4900
Range 3270–9650 3600–8280 3530–6740 4170–6800

AUC0–last=the area under the serum concentration versus time curve from time 0 to the last measurable concentration. AUC0–∞=the AUC extrapolated to infinity. Cmax=maximum
measured serum concentration over the time span specified. kel=apparent first-order elimination rate constant. t1/2=elimination or terminal half-life. Tmax=time of the
maximum measured serum concentration. Vd=volume of distribution.

Table 5: Summary of serum pharmacokinetic parameters of dengue monoclonal antibody

Premedication with antihistamines, paracetamol, cortico­
steroids, or a combination of these drugs is a common
practice to prevent infusion reactions with many
monoclonal antibodies. These drugs act as prophylaxis
for cytokine-release syndrome.19
Infusion reactions are more common with faster
infusions. Reducing the infusion rate (eg, for rituximab) is
recommended to reduce the reactions.20 In cohorts three
and four, the speed of the infusion was reduced and, as
expected, the reactions reduced substantially. In any case,
all these reactions were mild to moderate, and transient.
Five of the seven lymphopenias occurred in cohort four
and one each occurred in cohort two and cohort three.
None of the lymphopenias were associated with any
symptoms. Dengue monoclonal antibody did not show
any tissue cross-reactivity in preclinical studies, and
hence it is not expected to bind to any human tissues.
The reasons for this toxicity at the highest dose of
12 mg/kg are not known. Lymphopenia was not observed
in the preclinical studies. In any case, this highest dose
of 12 mg/kg will not be used in future clinical studies of
dengue monoclonal antibody.
Monoclonal antibodies are in use for the treatment of
several diseases. One of the limitations associated with
these monoclonal antibodies is the development of
immune response (ie, ADA response), which could
constitute a clinically significant problem.21 ADAs have
the potential to affect the pharmacokinetic and pharmaco­
dynamic profile of a monoclonal antibody, which could
affect drug efficacy and safety.22 ADAs are more common
with murine and chimeric than with humanised and
human monoclonal antibodies.23 None of the participants

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in our study had an ADA response against dengue
monoclonal antibody.
Peak and total exposure pharmacokinetic parameters
were dose-dependent, which indicates a linear
relationship between the dose and concentration. Higher
concentrations were not associated with any serious
safety concerns or toxicity except for lymphopenia in
cohort four, which was not associated with any symptoms
or concomitant infections. The half-life (t1/2), clearance,
and Vd were independent of dose, indicating no effect of
dose on these parameters.
No antiviral drug has been approved despite the
association between higher viraemia and severe dengue.13
Therapeutic monoclonal antibodies provide a potentially
important approach to the treatment of dengue.13 Drugs
such as chloroquine,24 prednisolone,25 balapiravir,26
celgosivir,27 lovastatin,28 and ivermectin29 have been tested
in clinical trials and none of them showed any efficacy.
Although ivermectin showed a statistically significant
difference in terms of NS1 antigen clearance compared
with placebo, there was no effect on viraemia and other
clinical efficacy endpoints.29 The possible reasons for
their failure to meet efficacy could be an insufficient
potent antiviral activity, and dose-limiting toxicity.
Dengue monoclonal antibody has shown very strong
neutralisation of all four dengue virus serotypes in in-
vitro and in-vivo animal studies, binds to the most
conserved region of EDIII protein on dengue virus, and
has a long half-life of about 32 days, thus enabling it to
overcome the limitations of small molecule therapeutic
agents. In 2023, another molecule (JNJ-1802) was
evaluated for safety in a phase 1 study.30
The study was conducted in Adelaide, SA, Australia (ie,
a non-endemic region) to mitigate the theoretical risk of
ADE with this monoclonal antibody in a population with
pre-existing antibodies against dengue. Moreover, these
participants had an extremely low risk of exposure to
dengue infection due to being in a non-endemic region.
There is concern of ADE in dengue and with dengue
vaccines. However, dengue monoclonal antibody is
eliminated from the body within four to five half-lives (ie,
around 120–150 days). Moreover, dengue monoclonal
antibody neutralises all four dengue virus serotypes,
which is different from infection or vaccine-induced
antibodies that are serotype-specific. Therefore, there
might not be a concern of ADE with this antibody. No
ADE was seen in animal studies as well.16,18
This study had many strengths. This is the first
published clinical study of any dengue monoclonal
antibody globally. The study was conducted in a dengue-
naive population in a non-endemic country to assess this
antibody without any background interference by natural
dengue antibodies. The study involved strict safety
monitoring; participants were closely observed for 4 days
after administration of study drug. The dose escalations
were done after careful review of safety data for each
preceding dose and sentinel cohorts. This study had a
10 www.thelancet.com/infection Published online February 23, 2024 https://doi.org/10.1016/S1473-3099(24)00030-6
few limitations. A dengue rapid kit was used at screening
for inclusion of individuals who were dengue-naive,
which has a limitation of sensitivity. This limitation
could have led to the inclusion of one participant in
cohort four who had high dengue monoclonal antibody
concentration at baseline, possibly suggesting false
negative result by the rapid kit. However, inclusion or
exclusion of this participant did not affect the results of
the pharmaco­ kinetic analysis. Only four female
participants were enrolled, possibly due to the
requirement of five days’ stay in the clinical trial unit.
The majority of participants were White because the
study was conducted in Australia. Hence, safety and
pharmacokinetic profile could not be evaluated in other
populations. However, since these are recombinant
proteins, we do not anticipate any effect of race or
ethnicity on the action of the antibody. The first cohort
had no placebo control because the intention was to
assess the dose-independent effects of dengue
monoclonal antibody before proceeding to higher doses.
To conclude, a single dose of dengue monoclonal
antibody in the range of 1 mg/kg to 12 mg/kg,
administered as intravenous injection or infusion, was
safe and well tolerated in this study. Currently, there is no
therapeutic option available for dengue. Dengue
monoclonal antibody is now being evaluated in a phase 2
trial in patients with mild to moderate dengue to assess
safety and efficacy.
Contributors
PSK, BG, NF, CSP, SSP, and RMD contributed to the study design and
protocol development. All authors had full access to all the data in the
study. BG and PSK accessed and verified the data. PSK and BG
contributed to the manuscript preparation with considerable inputs
from all the authors. NF contributed to data collection. CDK, SSP, and
BG contributed to pharmacokinetic and anti-drug antibody experiment
oversight and supervision. CM contributed to pharmacokinetic analysis
and provided inputs to the manuscript. All authors had final
responsibility for the decision to submit the manuscript.
Declaration of interests
CSP is the Chairman and Managing Director of the Serum Institute of
India (Pune, India), which is the manufacturer of the dengue
monoclonal antibody. PSK, BG, CDK, SSP, and RMD are employed by
the Serum Institute of India. RMD and SSP are inventors on patent
application PCT/IB2017/058194 detailing the formulation and
manufacturing process of dengue monoclonal antibody (known
previously as VIS513). During the conduct of the study, CM was
working with PPD (Cambridge, UK). CM is currently employed by
AstraZeneca. NF declares no competing interests.
Data sharing
The anonymised study protocol is provided in the appendix (pp 12–132).
Individual de-identified participant data will be made available on direct
request to the corresponding author with an appropriate research
proposal. These data will be shared upon approval of analysis proposals
and when signed data-access agreements are in place.
Acknowledgments
The study was funded by the Serum Institute of India (Pune, India).
We gratefully acknowledge the contribution of the study participants.
We acknowledge the contribution of staff from CMAX Clinical Research
(Adelaide, SA, Australia) towards participant recruitment and data
collection. We acknowledge Peter Slobodian, Lead Clinical Trials
Pharmacist at Royal Adelaide Hospital (Adelaide, SA, Australia) for his
role in preparation of study products and masking of the study product.

We also acknowledge PPD for clinical monitoring and data management
services.
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