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44 Scientific American, April 2019

SOURCE: “EFFECT OF DENGUE SEROSTATUS ON DENGUE VACCINE SAFETY AND EFFICACY,”

BY SARANYA SRIDHAR ET AL., IN

NEW ENGLAND JOURNAL OF MEDICINE,

VOL. 379, NO. 4; JULY 26, 2018

Graphic by Amanda Montañez

her team, including statistical mod-
eler Leah Katzelnick, was studying
the ways in which dengue sickens
children. That goal then led the re-
searchers to help establish a lab in
Nicaragua and to begin one of the
more challenging types of scientific
projects: a long-term pediatric co-
hort study. Harris and her associ-
ates in Managua, Nic aragua’s capi-
tal city, had the not so easy task of
following thousands of children.
For more than 15 years the sci-
entists working on the Nicaraguan
Pediatric Dengue Cohort Study
cared for the children if they got
sick and went to their homes to
collect data and blood samples.
Out of 6,684 subjects, the research-
ers found 618 who had been sick
with dengue and nearly four dozen
who developed severe disease.
Scouring more than 41,000 blood
samples, taken over more than a
dozen years, they made a striking
discovery. Children with a specific
concentration of antibodies—not
low enough to be useless, not high
enough to offer protection, but a
concentration of antibodies in a
middling range—were at a nearly
eight times higher risk of acquir-
ing dengue hemorrhagic fever and
dengue shock syndrome.
ADE handily explains this find-
ing. If the antibodies are not there
to begin with or are present at very
low densities, they cannot enhance
a subsequent dengue infection to
cause serious disease. If antibodies
are present at high densities (as
happens shortly after an initial in-
fection), they somehow manage to
cover any new dengue virus suffi-
ciently to disable it, enabling mac-
rophages to kill it. If, however, the
antibody concentrations are in what Harris describes as a “dan-
ger zone”—not low and not high—they may facilitate the virus’s
entry into the macrophages without disarming it, thereby accel-
erating virus production.
Harris’s Science paper describing these results was, in the
words of Jean Lim, a virologist at the Icahn School of Medicine
at Mount Sinai, a “rock star study” that swayed some of the
staunchest naysayers of ADE. Her unexpected findings may
also have hit on the solution to the dengue vaccine mystery.

A RED FLAG
CoinCidentally, days aFter Harris’s paper was published in No-
vember 2017, Sanofi Pasteur made the announcement that en-

raged Filipino parents: do not get Dengvaxia if you have not

had dengue. A month later the WHO followed suit, stating that

only individuals who were proved to already have had dengue

should be given the vaccine.

That was exactly what Halstead had been saying since March

2016, when he published an analysis in Vaccine arguing that

Dengvaxia might cause harm. Perhaps in people who had never

had dengue, the vaccine was acting like a first dengue infection,

priming the body with just the right quantity of Trojan-horse an-

tibodies to help a real infection turn severe. Young children were

less likely to have already encountered dengue, and for them, the

vaccine was more likely to act as a first infection. They were also

more likely than adults to develop severe dengue after a second

0 1 2 3 4 5

7

6

4

3

1

5

2

0

1

2

0

0 1 2 3 4 5

Percent of Study Participants Hospitalized for Dengue

Years after First Dose of Dengvaxia

Ages 2− 8

Ages 9− 16

Vaccine, no previous infection

No vaccine, previous infection

No vaccine, no previous infection

Vaccine, previous infection

Because of safety concerns in

younger children, Sanofi Pasteur

now recommends Dengvaxia for

children older than nine who are

documented to have experienced

a previous dengue infection.

How Safe Is Dengvaxia?

Using a newly developed test, Sanofi Pasteur researchers evaluated which of the children

in its clinical trials for Dengvaxia, the first ever licensed vaccine for dengue, had experi­

enced a dengue infection prior to vaccination. They found that if a child had a pre vious

infection ( blue lines ), the vaccine was very effective in protecting him or her against hospi­

talization for dengue. If, however, the child had no sign of a previous dengue infection

( red lines ), he or she was far more likely than unvaccinated children of the same age group

to be hospitalized with serious dengue fever, years after vaccination. The effect was far

more pronounced in younger children ( top graph ), who are more likely than older children

( bottom graph ) to develop severe dengue in the first place.