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
[email protected]
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 infections and 40 467 (95% CI 17 620–49 778) deaths due
disease of humans. The WHO regions of the Americas, to dengue in 2017.2
South-East Asia, and Western Pacific are the most Dengue was responsible for around 500 000 admissions
seriously affected. Globally, dengue cases have increased to hospital for treament3 and about 2∙38 million
from about 30 million in 1990 to about 56 million in 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

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Research in context
Evidence before this study Added value of this study
The majority of antibodies in individuals infected with dengue This is the first worldwide report on the safety and
virus are against the immunodominant epitopes of envelope pharmacokinetics of dengue monoclonal antibody in healthy
protein and premembrane protein, which could be involved in adults. Almost all adverse events were mild to moderate and
antibody-dependent enhancement of dengue. Dengue resolved completely. Slowing the rate of infusion and
monoclonal antibody (earlier known as VIS513) is an premedication with 1 g oral paracetamol about 30 min before
engineered humanised monoclonal antibody that binds to a the start of infusion abrogated infusion-related reactions such
non-immunodominant epitope on domain III of envelope as fever, chills, and rigors. Dengue monoclonal antibody was
protein (EDIII). Dengue monoclonal antibody has shown found to be safe and well tolerated with no serious safety
specific neutralisation of all four serotypes of dengue virus in concerns reported. Dengue monoclonal antibody showed a
in-vivo animal models and in-vitro studies. Dengue monoclonal dose-dependent increase in pharmacokinetic exposure without
antibody was safe and no toxicity was observed in preclinical any anti-drug antibody response.
studies in mice, rats, rabbits, and non-human primates at doses
Implications of all the available evidence
up to 400 mg/kg. Technology to manufacture dengue
There is no therapeutic approved for the treatment of dengue.
monoclonal antibody was transferred to India. We searched
Current treatment includes maintenance of hydration and
PubMed for clinical trials published from Jan 1, 2008, to
symptomatic treatment. The safety of dengue monoclonal
Aug 19, 2023, with no language restrictions, using the terms
antibody in healthy adults, as shown by this study, will now
“dengue monoclonal antibody” and “clinical trial”. We found no
pave the way forward for evaluation of its efficacy and safety in
clinical trial publications on dengue monoclonal antibody.
a phase 2 study in patients with dengue.
This monoclonal antibody is being developed for therapeutic
use in dengue.

dengue is increasing due to factors such as climate homotypic dengue virus infection but only short-term
change, globalisation, and viral evolution,4 and is immunity against heterotypic dengue virus infec­ tion.
emerging as a health problem for international After waning, these antibodies can be involved in
travellers.5,6 antibody-dependent enhancement (ADE) with hetero­
There are four distinct dengue virus serotypes (ie, typic dengue virus infection.14,15 Therefore, therapeutic
DENV-1, DENV-2, DENV-3, and DENV-4), with most monoclonal anti­ bodies for dengue should be able to
endemic countries reporting circulation of all four neutralise all four dengue virus serotypes. Dengue
serotypes.7 Dengue virus contains three structural monoclonal antibody (VIS513) is an engineered
proteins: premembrane, capsid, and envelope (containing humanised monoclonal antibody that binds to a non-
domain I, domain II, and domain III), and seven non- immunodominant epitope on domain III of the envelope
structural proteins.8 Dengue presentation ranges from protein (EDIII) and has shown potent, specific neutra­
dengue with or without warning signs to severe dengue.7 lisation of all four serotypes of dengue virus.16 The
There is currently no specific treatment for dengue and antibody has shown activity in multiple in-vivo models of
preventive measures include mosquito control. Two dengue infection.16–18 The antibody was shown to
vaccines (Dengvaxia, Sanofi Pasteur, France; and Qdenga, overcome ADE both in vitro and in vivo with minimal, if
Takeda, Germany) have been licensed in a few countries, any, enhancement of in-vitro infectivity.18 Dengue
albeit with some limitations. Dengvaxia has shown lower monoclonal antibody is a therapeutic and is not intended
efficacy for DENV-1 and DENV-2 and is recommended for prophylactic use, and the antibody titres will wane
only in individuals with previous dengue infection.9,10 No during the umbrella of protection provided by the host
efficacy of Qdenga was observed for DENV-3 in response to the treated infection.
participants who were seronegative at baseline and there Dengue monoclonal antibody is produced by
were too few cases to conclude efficacy against DENV-4.11 recombinant DNA technology in a mammalian cell (ie,
Current management of dengue includes supportive Chinese hamster ovary) line in the USA. After a
care in the form of fluid replacement and close clinical technology transfer, the manufacturing and formulation
monitoring.12 Thus, effective anti-dengue treatments are was optimised in India. Animal toxicity studies did not
an unmet medical need. show any toxicity. After this evidence, we conducted the
Based on structural and non-structural proteins, first-in-human study in healthy adults in Australia.
antiviral therapeutics against dengue are under develop­ The primary objective was to assess the safety and
ment.13 The majority of the naturally acquired dengue tolerability of dengue monoclonal antibody, whereas
antibodies are against the immunodominant epitopes of the secondary objectives were to assess pharmacokinetic
the envelope protein fusion loop and the premembrane parameters and anti-drug antibodies (ADAs) to dengue
proteins that provide long-term immunity against monoclonal antibody.

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Study group Dose Number of participants Allocation ratio

Cohort one (initial safety cohort) Dengue monoclonal antibody 1 mg/kg 4 Not applicable
Cohort two Dengue monoclonal antibody; placebo 3 mg/kg; 3 mg/kg 10; 2 1:1 for sentinel cohort (n=2) and 9:1 for expansion cohort (n=10)
Cohort three Dengue monoclonal antibody; placebo 7 mg/kg; 7 mg/kg 10; 2 1:1 for sentinel cohort (n=2) and 9:1 for expansion cohort (n=10)
Cohort four Dengue monoclonal antibody; placebo 12 mg/kg; 12 mg/kg 10; 2 1:1 for sentinel cohort (n=2) and 9:1 for expansion cohort (n=10)

Table 1: Treatment allocation

Methods two to four, the participants, investigator, and outcome

Study design and participants assessors were masked. The laboratories analysing the
This was a partially blind (observer-blind), randomised, samples were also masked.
placebo-controlled, phase 1, single ascending dose trial in RAH Pharmacy staff prepared the study products
healthy adults. The study was conducted at CMAX (dengue monoclonal antibody or placebo for respective
Clinical Research, which is a dedicated phase 1 clinical cohorts) which were transferred to CMAX Clinical
research unit based in Adelaide, SA, Australia. This Research in black plastic bags to maintain masking. The
facility was contracted by Serum Institute of India (Pune, infusion bag was kept at ambient temperature (ie,
India) for the conduct of this study. The study was below 25°C) for about 20–30 min before dosing.
conducted from March to December, 2019, and was
approved by Bellberry Human Research Ethics Procedures
Committee. The study followed the Good Clinical Dengue monoclonal antibody (manufactured by Serum
Practice Guidelines, Declaration of Helsinki, and the Institute of India [SIIPL], Pune, India) is a sterile, slightly
Australian National Statement on Ethical Conduct in yellowish, clear liquid packaged into clear glass vials of
Human Research. 30 mL. Each vial contains dengue monoclonal antibody
Healthy adults (aged 18–45 years) with negative dengue 25 mg/mL and excipients (batch 3148T0010Z, manu­
NS1 and dengue IgG antibodies who provided written facturing date June, 2018).
consent were included in the study. Presence of fever or The placebo (manufactured by SIIPL) was a formulation
acute infection, clinically significant disorders, and buffer containing all the same ingredients as dengue
allergic reactions to the study product were exclusion monoclonal antibody except for the active ingredient
criteria (appendix pp 73–75). (batch 3228T0010Z, manufacturing date June, 2018). See Online for appendix
Study products were stored between 2°C and 8°C.
Randomisation and masking 40 participants across five cohorts were dosed with
There were five cohorts with doses of 1 mg/kg (n=4), dengue monoclonal antibody or placebo and were
3 mg/kg (n=12), 7 mg/kg (n=12), 12 mg/kg (n=12), and followed up until day 85. Dose escalations occurred after
25 mg/kg (n=12) of dengue monoclonal antibody review of safety data after 7 days by the Protocol Safety
(table 1). In cohort one, four participants were Review Team comprising the principal investigator,
administered 1 mg/kg dengue monoclonal antibody sponsor physicians, and a statistician. Dengue mono­
sequentially. For each of the other four cohorts, there clonal antibody doses evaluated in the study were selected
were two sub-cohorts: a sentinel cohort (n=2) and an on the basis of safety in preclinical studies at doses
expansion cohort (n=10). In sentinel sub-cohorts, ranging from 3 mg/kg to 400 mg/kg. An initial dose of
participants were randomly assigned (1:1) to dengue 1 mg/kg was selected to assess any dose-independent
monoclonal antibody or placebo. In the expansion sub- effect of dengue monoclonal antibody. The cohort for the
cohorts, the remaining ten participants were randomly 25 mg/kg dose, cohort five, was not enrolled for safety
assigned (9:1) to dengue monoclonal antibody or placebo reasons because the 12 mg/kg dose caused more adverse
(table 1). Unequal allocation to dengue monoclonal events than a lower dose, although almost all adverse
antibody and placebo ensured generation of safety data events were mild to moderate in severity.
on dengue monoclonal antibody in more participants. Volunteers were screened for up to 28 days before
A computer-generated randomisation schedule pre­ being randomly assigned on day 1. The eligible
pared by an independent team was provided to the participants were admitted to CMAX Clinical Research a
unmasked pharmacist at Royal Adelaide Hospital (RAH) day before randomisation until day 5 (ie, 96 h after
Pharmacy (Adelaide, SA, Australia) who had no further administration of study drug). On day 1, a single dose
involvement in the trial. Study drugs were dispensed by of dengue monoclonal antibody or placebo was
the unmasked pharmacist to CMAX Clinical Research. administered as an intravenous injection or infusion
This was a partially blind (observer-blind) study. In (table 1).
cohort one, masking was not applicable because there After discharge on day 5, participants visited CMAX six
was no control group, which meant that all participants times over a period of 84 days (days 6, 8, 15, 29, 57,
were to receive dengue monoclonal antibody. For cohorts and 85).

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The safety assessments included any hypersensitivity

125 participants screened for eligibility reactions including infusion reactions within 4 h of
infusion, adverse events and serious adverse events
85 excluded (SAEs) throughout the study period of 84 days, clinical
51 inclusion criteria not met chemistry and haematology (baseline, day 2, day 5, day 8,
or exclusion criteria met
20 withdrawal by
and day 29) and ADAs against dengue monoclonal
participant antibody (baseline, day 29, and day 85). Severity of
4 lost to follow-up adverse events was rated according to the Division of
4 additional participants
screened AIDS Toxicity Grading criteria.
2 withdrawal by Clinical chemistry, haematology, and baseline dengue
investigator
4 out of screening window
(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).
40 participants randomly assigned A quasi-quantitative validated ELISA method was used
for the measurement of ADAs against dengue
monoclonal antibody in sera samples. The lower limit of
34 assigned to dengue monoclonal 6 assigned to placebo
detection (LLOD) for this assay was 133∙57 ng/mL for the
antibody screening assay and 64∙91 ng/mL for the confirmatory
assay.
Samples for pharmacokinetics were collected at
34 included in safety population 6 included in safety population
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
34 included in pharmacokinetic day 85. Dengue monoclonal antibody concentration in
population sera samples was measured using a validated
colorimetric ELISA, in which high-binding microtitre
34 completed study 6 completed study plates were coated with murine anti-dengue monoclonal
antibody (capture antibody) to capture dengue mono­
Figure: Participant flowchart clonal antibody in the sera samples. The LLOD was
40 ng/mL and the range of the assay was 40–1600 ng/mL
Safety was monitored by assessment of vital signs, (appendix p 2).
physical examination, laboratory testing (haematology Pharmacokinetic and ADA sample analysis was
and chemistry), and electrocardiograms (ECGs) at conducted at Syngene International (Benguluru, India).
periodic intervals (appendix pp 55–57).
For cohort one, dengue monoclonal antibody doses Outcomes
were administered as a slow intravenous injection without The primary outcomes were proportion of participants
dilution in up to 3 min. For cohorts two to four, dengue with adverse events, SAEs, discontinuations due to
monoclonal antibody or placebo were given by intravenous adverse events, post-infusion adverse events within 4 h of
infusion using an infusion bag and intravenous line. The dosing, and clinically significant abnormal safety
total volume of study products was a calculated dose based laboratory findings. The secondary outcomes were the
on bodyweight plus priming volume in intravenous line pharmacokinetic profile of dengue monoclonal antibody
of 23 mL. The study product was then transferred into an (maximum measured serum concentration over the time
empty infusion bag and was connected to an infusion span specified [Cmax], time of the maximum measured
pump. The total dose was administered over a period of serum concentration [Tmax], the area under the serum
10–30 min for cohort two, 1 h for cohort three, and 1–2 h concentration versus time curve [AUC] from time 0 to
for cohort four. The dose calculation and administration the last measurable concentration [AUC0–last], the AUC
for placebo was followed in the same manner as that for extrapolated to infinity (AUC0–∞), elimination or terminal
the respective dengue monoclonal antibody cohort. half-life [t1/2], volume of distribution [Vd], clearance, and
Both before and after the administration of study apparent first-order elimination rate constant [kel]) and
products, 5 mL of formulation buffer (same as placebo) the development of any ADA to dengue monoclonal
was administered to all participants. This formulation antibody.
buffer was administered to ensure that intravenous access
was patent before infusion and to ensure that no drug Statistical analysis
remained in the cannula after infusion of the study drug. Being a phase 1 trial, the study was not powered. It was
All participants in cohort three and cohort four were planned to have at least ten participants in each dose
administered 1 g of paracetamol orally as premedication group of dengue monoclonal antibody and the placebo
about 30 min before dosing to minimise infusion controls for each cohort were pooled together as a control
reactions. 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 Role of the funding source
descriptively. The funder of the study was involved in study design,
For categorical variables, frequencies and percentages data interpretation, and writing of the report, but was not
were presented. Continuous variables were summarised involved in data collection and data analysis. All the
using descriptive statistics (mean, SD, minimum, and authors had full access to the data.
maximum).
Safety data were analysed by group as total number of Results
adverse events and participants with at least one adverse The study was conducted from March 22 to Dec 23, 2019.
event (n and percentage). 125 participants were screened for eligibility, of whom
Dengue monoclonal antibody concentration data were 40 (32%) were randomly assigned. All participants
summarised using descriptive statistics (n, geometric completed the study follow-up (figure).
mean, median, minimum, and maximum) by sampling 40 participants were part of the safety population and
timepoint and dose. Non-compartmental analysis was 34 participants were part of the pharmacokinetic
used to calculate the pharmacokinetic parameters of population (figure).
dengue monoclonal antibody. This analysis was done Most of the participants were White (n=36, 90%) and
using Phoenix WinNonlin version 8.0 (Pharsight, male (n=36, 90%). The mean age was 28∙1 years (SD 7∙0)
St Louis, MO, USA). and mean weight was 77∙1 kg (11∙3; table 2). All
The ADA response was defined as a participant with a 40 participants were negative for ADA at baseline.
baseline negative ADA status converting to a positive Only two major protocol deviations were reported: one
ADA status after study drug administration or a two-fold participant missed day 6 and day 15 visits and one
rise in ADA titres after study drug administration in participant’s day 5 haematology tests could not be
participants who had baseline ADA-positive status. conducted owing to sample collection in a wrong container.
The safety population included all participants who 24 participants had at least one minor protocol deviation.
were enrolled and received a study drug. The safety These deviations were mostly related to procedures done
population was used in the safety analyses. The outside of the protocol-allowed window by a few minutes
pharmacokinetic population included participants who for most of the participants (appendix pp 5–7), which were
received dengue monoclonal antibody and had not expected to have substantial effects on the study
concentration data available. outcomes, as based on clinical judgement of the
All statistical analyses were conducted using SAS investigator and sponsor medical officers.
version 9.4; see appendix for details (pp 133–62). The trial There were no SAEs in the study and no adverse events
is registered with ClinicalTrials.gov, NCT03883620. that led to study withdrawal. No adverse events were

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

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

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cohort four). For the participant from cohort three, respectively) and the median AUC0–∞ (13 700 h*μg/mL,
baseline and day 2 ALC were 1∙4 × 10⁹ per L (normal) and 47 000 h*μg/mL, 127 000 h*μg/mL, and 207 000 h*μg/mL
0∙3 × 10⁹ per L (grade 4), respectively, which rose to for the four dose groups, respectively). Tmax values were
0∙6 × 10⁹ per L (grade 1) on day 8 and day 29. For the variable across the four dose groups: 0∙13 h (1 mg/kg
participant from cohort four, baseline and day 2 ALC dose), 0∙59 h (3 mg/kg dose), 5∙06 h (7 mg/kg dose), and
were 1∙4 × 10⁹ per L (normal) and 0∙3 × 10⁹ per L (grade 4), 2∙25 h (12 mg/kg dose). The half-life (t1/2) was similar
respectively, and 0∙7 × 10⁹ per L (normal), 0∙6 × 10⁹ per L across dose groups: 775 h (1 mg/kg dose), 877 h (3 mg/kg
(grade 1), and 0∙9 × 10⁹ per L (normal) on day 5, day 8, dose), 830 h (7 mg/kg dose), and 878 h (12 mg/kg dose).
and day 29, respectively. Vd, clearance, and kel were also similar across all dose
136 (95%) of 143 adverse events were completely groups (table 5).
resolved. Seven (5%) adverse events in five participants Except for one participant, all participants had dengue
were either not resolved or were resolving at the last visit. monoclonal antibody concentration below the LLOD (ie,
Of these seven adverse events, four were treatment- below 40 ng/mL) before infusion of dengue monoclonal
related—three events of lymphopenia and one of orchitis. antibody. This participant had a baseline dengue
At the last follow-up visit, all participants with monoclonal antibody concentration of 69∙6 μg/mL, a
lymphopenias were without any symptoms and they Cmax of 382 μg/mL, a Tmax of 2∙5 h, and an AUC0–last
were grade 1 (ie, ALC ≥0∙6 × 10⁹ per L). Of the seven 127 000 h*μg/mL that was similar to all other participants.
ongoing adverse events, three unrelated adverse events Pharmacokinetic analysis did not show any difference
included an upper respiratory tract infection in one when this participant was excluded or included in the
participant, and rotator cuff syndrome and fatigue in analysis of dose proportionality in terms of Cmax, and
another participant. AUC0–last, and dose independence in terms of clearance
There were no clinically significant changes in (appendix pp 9–11).
haematology, clinical chemistry, and urinalysis para­ None of the participants developed ADA response.
meters except for seven participants with lymphopenia
and one participant with thrombocytopenia. Lympho­ Discussion
penia was seen in five participants from cohort four and To our knowledge, this was the first-in-human randomised,
one each in cohort two and cohort three. Of these partially blind (observer-blind), placebo-controlled, single
participants, three had grade 2 lymphopenia, two had ascending dose study of dengue monoclonal antibody in
grade 3 lymphopenia, and two had grade 4 lymphopenia. healthy adults. Dengue monoclonal antibody administered
However, this decrease in lymphocytes was not associated at doses ranging from 1 mg/kg to 12 mg/kg as an
with any clinical symptoms. Concentrations of intravenous injection or infusion was safe and well
lymphocytes showed a rise on day 5 in all participants tolerated. Dengue monoclonal antibody also showed dose-
with lymphopenia. proportionate pharmaco­ kinetic exposure. Headache,
No clinically significant changes in blood pressure, infusion reaction, lympho­penia, fatigue, and pyrexia were
pulse rate, respiratory rate, and tympanic temperature the most common adverse reactions. Almost all adverse
were observed except for those changes related to events were of grade 1 or grade 2 severity, and resolved
infusion reactions, tachycardia, and increased blood completely. No deaths, SAEs, or adverse events causing
pressure in a few participants, which were transient. premature discontinuation were observed.
No clinically significant changes were detected on ECG Most of the adverse events within 4 h of dosing were
conducted post-infusion compared with baseline, except related to the infusion and included headache,
for three participants who had increased heart rate due to dizziness, lethargy, tremor, infusion reaction, fatigue,
infusion. One participant from cohort two had postural catheter site pruritus, tachycardia, nausea, vomiting,
orthostatic tachycardia syndrome that occurred about neck pain, and peripheral coldness. One of the known
7∙5 h after the end of infusion and resolved within 4∙5 h. adverse reactions with approved monoclonal antibodies
Two participants from cohort four had tachycardia. One is the infusion reactions. Infusion reactions can cause
of these participants had tachycardia that occurred about chills, fever, mild hypotension, dyspnoea, and rash.
2∙0 h after the end of infusion and resolved in about Rarely, severe reactions could cause severe hypotension,
6∙0 h. The other participant had tachycardia that occurred anaphylaxis, and cardiac dysfunction. An infusion
about 5∙0 h after the end of infusion and resolved in reaction usually starts within 30–120 min after the start
about 1∙0 h. These changes did not require any of administration of the monoclonal antibody, but
intervention and resolved completely. These events were delayed infusion reactions at up to 24 h can occur.
mild and related to the study drug. When the monoclonal antibodies bind to the target cell,
There was a dose-proportionate increase in the Cmax cytokines are released into the circulation that cause
(28 μg/mL, 91 μg/mL, 210 μg/mL, and 525 μg/mL for the the typical symptoms.19
four dose groups, respectively), the median AUC0–last With administration of paracetamol 1 g as pre­
(12 000 h*μg/mL, 38 400 h*μg/mL, 104 000 h*μg/mL, medication in cohorts three and four, these adverse events
and 168 000 h*μg/mL for the four dose groups, 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 hence it is not expected to bind to any human tissues.
steroids, or a combination of these drugs is a common The reasons for this toxicity at the highest dose of
practice to prevent infusion reactions with many 12 mg/kg are not known. Lymphopenia was not observed
monoclonal antibodies. These drugs act as prophylaxis in the preclinical studies. In any case, this highest dose
for cytokine-release syndrome.19 of 12 mg/kg will not be used in future clinical studies of
Infusion reactions are more common with faster dengue monoclonal antibody.
infusions. Reducing the infusion rate (eg, for rituximab) is Monoclonal antibodies are in use for the treatment of
recommended to reduce the reactions.20 In cohorts three several diseases. One of the limitations associated with
and four, the speed of the infusion was reduced and, as these monoclonal antibodies is the development of
expected, the reactions reduced substantially. In any case, immune response (ie, ADA response), which could
all these reactions were mild to moderate, and transient. constitute a clinically significant problem.21 ADAs have
Five of the seven lymphopenias occurred in cohort four the potential to affect the pharmacokinetic and pharmaco­
and one each occurred in cohort two and cohort three. dynamic profile of a monoclonal antibody, which could
None of the lymphopenias were associated with any affect drug efficacy and safety.22 ADAs are more common
symptoms. Dengue monoclonal antibody did not show with murine and chimeric than with humanised and
any tissue cross-reactivity in preclinical studies, and human monoclonal antibodies.23 None of the participants

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in our study had an ADA response against dengue few limitations. A dengue rapid kit was used at screening
monoclonal antibody. for inclusion of individuals who were dengue-naive,
Peak and total exposure pharmacokinetic parameters which has a limitation of sensitivity. This limitation
were dose-dependent, which indicates a linear could have led to the inclusion of one participant in
relationship between the dose and concentration. Higher cohort four who had high dengue monoclonal antibody
concentrations were not associated with any serious concentration at baseline, possibly suggesting false
safety concerns or toxicity except for lymphopenia in negative result by the rapid kit. However, inclusion or
cohort four, which was not associated with any symptoms exclusion of this participant did not affect the results of
or concomitant infections. The half-life (t1/2), clearance, the pharmaco­ kinetic analysis. Only four female
and Vd were independent of dose, indicating no effect of participants were enrolled, possibly due to the
dose on these parameters. requirement of five days’ stay in the clinical trial unit.
No antiviral drug has been approved despite the The majority of participants were White because the
association between higher viraemia and severe dengue.13 study was conducted in Australia. Hence, safety and
Therapeutic monoclonal antibodies provide a potentially pharmacokinetic profile could not be evaluated in other
important approach to the treatment of dengue.13 Drugs populations. However, since these are recombinant
such as chloroquine,24 prednisolone,25 balapiravir,26 proteins, we do not anticipate any effect of race or
celgosivir,27 lovastatin,28 and ivermectin29 have been tested ethnicity on the action of the antibody. The first cohort
in clinical trials and none of them showed any efficacy. had no placebo control because the intention was to
Although ivermectin showed a statistically significant assess the dose-independent effects of dengue
difference in terms of NS1 antigen clearance compared monoclonal antibody before proceeding to higher doses.
with placebo, there was no effect on viraemia and other To conclude, a single dose of dengue monoclonal
clinical efficacy endpoints.29 The possible reasons for antibody in the range of 1 mg/kg to 12 mg/kg,
their failure to meet efficacy could be an insufficient administered as intravenous injection or infusion, was
potent antiviral activity, and dose-limiting toxicity. safe and well tolerated in this study. Currently, there is no
Dengue monoclonal antibody has shown very strong therapeutic option available for dengue. Dengue
neutralisation of all four dengue virus serotypes in in- monoclonal antibody is now being evaluated in a phase 2
vitro and in-vivo animal studies, binds to the most trial in patients with mild to moderate dengue to assess
conserved region of EDIII protein on dengue virus, and safety and efficacy.
has a long half-life of about 32 days, thus enabling it to Contributors
overcome the limitations of small molecule therapeutic PSK, BG, NF, CSP, SSP, and RMD contributed to the study design and
agents. In 2023, another molecule (JNJ-1802) was 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
evaluated for safety in a phase 1 study.30 contributed to the manuscript preparation with considerable inputs
The study was conducted in Adelaide, SA, Australia (ie, from all the authors. NF contributed to data collection. CDK, SSP, and
a non-endemic region) to mitigate the theoretical risk of BG contributed to pharmacokinetic and anti-drug antibody experiment
ADE with this monoclonal antibody in a population with oversight and supervision. CM contributed to pharmacokinetic analysis
and provided inputs to the manuscript. All authors had final
pre-existing antibodies against dengue. Moreover, these responsibility for the decision to submit the manuscript.
participants had an extremely low risk of exposure to
Declaration of interests
dengue infection due to being in a non-endemic region. CSP is the Chairman and Managing Director of the Serum Institute of
There is concern of ADE in dengue and with dengue India (Pune, India), which is the manufacturer of the dengue
vaccines. However, dengue monoclonal antibody is monoclonal antibody. PSK, BG, CDK, SSP, and RMD are employed by
eliminated from the body within four to five half-lives (ie, the Serum Institute of India. RMD and SSP are inventors on patent
application PCT/IB2017/058194 detailing the formulation and
around 120–150 days). Moreover, dengue monoclonal manufacturing process of dengue monoclonal antibody (known
antibody neutralises all four dengue virus serotypes, previously as VIS513). During the conduct of the study, CM was
which is different from infection or vaccine-induced working with PPD (Cambridge, UK). CM is currently employed by
antibodies that are serotype-specific. Therefore, there AstraZeneca. NF declares no competing interests.

might not be a concern of ADE with this antibody. No Data sharing

The anonymised study protocol is provided in the appendix (pp 12–132).
ADE was seen in animal studies as well.16,18
Individual de-identified participant data will be made available on direct
This study had many strengths. This is the first request to the corresponding author with an appropriate research
published clinical study of any dengue monoclonal proposal. These data will be shared upon approval of analysis proposals
antibody globally. The study was conducted in a dengue- and when signed data-access agreements are in place.
naive population in a non-endemic country to assess this Acknowledgments
antibody without any background interference by natural The study was funded by the Serum Institute of India (Pune, India).
We gratefully acknowledge the contribution of the study participants.
dengue antibodies. The study involved strict safety
We acknowledge the contribution of staff from CMAX Clinical Research
monitoring; participants were closely observed for 4 days (Adelaide, SA, Australia) towards participant recruitment and data
after administration of study drug. The dose escalations collection. We acknowledge Peter Slobodian, Lead Clinical Trials
were done after careful review of safety data for each Pharmacist at Royal Adelaide Hospital (Adelaide, SA, Australia) for his
role in preparation of study products and masking of the study product.
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

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We also acknowledge PPD for clinical monitoring and data management 17 Ong EZ, Budigi Y, Tan HC, et al. Preclinical evaluation of VIS513,
services. a therapeutic antibody against dengue virus, in non-human
primates. Antiviral Res 2017; 144: 44–47.
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