Landmark study offers new insights into what protects against dengue

The precise elements of the immune response in a human physique that shield towards a dengue virus (DENV) an infection and the next sickness stay unclear. Scientists are nonetheless making an attempt to grasp how pure an infection and vaccination shield individuals in order that they will develop better vaccines.

Now, a novel examine has revealed necessary insights into creating sturdy immunity towards DENV, which is in any other case fairly complicated. Researchers from the US and Philippines have recognized particular antibodies, referred to as envelope dimer epitope (EDE)-like antibodies, as the important thing for constructing broad, cross-serotype immunity following pure an infection or vaccination.

The findings, revealed not too long ago in Science Translational Medicine, symbolize a major step ahead in understanding dengue immunity and will result in simpler therapeutics.

Illness burden and dengue vaccines

Dengue is a serious international well being problem attributable to any of 4 DENV serotypes (DENV1 to DENV4). It’s the commonest vector-borne viral illness, with half of the world’s inhabitants in danger, particularly in Southeast Asia, Africa, and the Americas. In response to one large study in 2013, the financial burden of dengue in Southeast Asia is greater than that of 17 different situations, together with Japanese encephalitis, higher respiratory infections, and hepatitis B.

And but creating a universally efficient vaccine has confirmed troublesome because of the complicated immune mechanisms concerned. In DENV circumstances, the preliminary immunity after first an infection (a.okay.a. main immunity) paradoxically will increase the danger of extreme illness moderately than conferring safety when an individual is contaminated a second time with a distinct serotype of the virus. This phenomenon, known as antibody-dependent enhancement, happens when non-neutralising antibodies bind to partially immature virus particles, facilitating their entry into immune cells and worsening the an infection. All extreme dengue circumstances requiring hospitalization outcome from such second infections.

Since vaccines mimic pure infections, the danger of antibody-dependent enhancement after the primary dose is the principle problem for dengue vaccines, which is why they’re normally really helpful just for people with prior publicity to the virus and prevented in dengue-naïve individuals.

After publicity to a minimum of two completely different DENV serotypes, an individual develops true safety, referred to as “secondary immunity”, towards future illness.

Presently, two main dengue vaccines are licensed (in some nations): Dengvaxia and QDENGA. These photographs are only for people who’ve already been uncovered to dengue a minimum of as soon as earlier than vaccination. Laboratory confirmation of a earlier dengue an infection is required for vaccination with Dengvaxia.

Outbreak in Cebu

DENV is an enveloped virus, which means it has a protecting outer layer. A key part of this layer is the envelope (E) protein, which is the first goal for the physique’s immune response.

The E protein is organized in pairs on the virus floor, creating complicated three-dimensional constructions referred to as quaternary epitopes. EDE is a important quaternary epitope and an necessary goal for vaccines and therapeutic antibodies.

In June 2017, Cebu province within the Philippines supplied a minimum of the primary dose of a dengue vaccine to kids aged 9-14 years. For the brand new examine, the researchers recruited and adopted a cohort of two,996 such kids. Of them, 1,782 acquired the primary dose of the vaccine and the remainder remained unvaccinated. The researchers collected baseline blood samples one month earlier than the vaccination marketing campaign and follow-up samples 17-28 months after the marketing campaign.

There had been an unusually giant dengue outbreak in Cebu between the baseline and follow-up pattern assortment, with most circumstances attributable to DENV2 (61.7%) adopted by DENV3 (30%). The researchers measured completely different sorts of antibodies within the samples: EDE-like antibodies (targetting envelope dimer epitopes); neutralising antibodies (which might block an infection by mature, absolutely fashioned viruses); and binding antibodies (people who connected to elements of the E protein with out essentially blocking an infection).

The examine targeted on the youngsters who had had proof of a minimum of two prior DENV infections (these with “secondary immunity”) on the baseline. They adopted up with the cohort as much as October 31, 2022, to test what number of with secondary immunity went on to develop dengue between the follow-up pattern assortment and the examine closure date. All of the samples had been analysed in vaccinated and unvaccinated kids on this subgroup in an try and reveal the true predictors of safety.

Extra protecting towards illness

The examine’s findings illuminated the position of EDE-like antibodies within the protecting response.

Particularly, the researchers discovered that EDE-like antibodies had been extremely prevalent in kids with secondary DENV immunity, with 81.8% to 90.1% of individuals having detectable ranges. This was in stark distinction to people with solely main DENV immunity, the place EDE-like antibodies had been largely absent (detected in solely 4% to 12% of circumstances). This implies EDE-like antibodies are an indicator of established immunity towards dengue. The magnitude of EDE-like antibodies was additionally strongly and persistently correlated with broad neutralisation of all 4 mature DENV serotypes, indicating that these antibodies are essential for widespread safety moderately than simply towards a single serotype.

The examine noticed that each pure DENV an infection — as a result of giant outbreak throughout the examine interval — and vaccination considerably boosted EDE-like antibodies in addition to normal DENV-binding and neutralising antibodies. This impact was evident even in kids who already possessed sturdy secondary immunity.

Crucially, greater ranges of EDE-like antibodies had been persistently related to decrease odds of symptomatic dengue, dengue with warning indicators, and dengue requiring hospitalisation. This protecting impact was noticed throughout a number of serotypes, demonstrating each serotype-specific and cross-reactive advantages. Nonetheless, EDE-like antibodies had restricted protecting results towards viral replication. Thus, they had been much less protecting towards new infections however extra protecting towards illness, particularly extreme illness.

Maybe essentially the most important discovering was that EDE-like antibodies didn’t simply correlate with safety: they statistically defined a considerable portion of the protecting impact seen with different mature virus-neutralising and E-binding antibodies. That’s, when EDE-like antibodies had been factored into statistical fashions, the protecting impact of different antibodies was considerably diminished whereas EDE-like antibodies remained strongly related to safety.

Particularly, EDE-like antibodies defined 42% to 65% of the protecting impact attributed to mature virus-neutralising antibodies and 41% to 75% of the impact of normal E protein-binding antibodies. This commentary strongly urged that EDE-like antibodies are a main, underlying determinant of broad, cross-reactive immunity towards dengue.

Limitations and the longer term

Though the examine had some limitations, reminiscent of a comparatively small variety of dengue circumstances for assessing safety towards all 4 serotypes and a restricted panel of monoclonal antibodies used for characterisation, it nonetheless marked a major advance within the combat towards dengue.

The staff supplied a clearer understanding of the immune responses that actually shield towards this debilitating illness. EDE-like antibodies additionally helped clarify how neutralising and binding antibodies contributed to safety.

Additional analysis will probably be important to formally validate EDE-like antibodies as dependable indicators of safety for vaccine efficacy trials. If that is validated, researchers will have the ability to design vaccines that particularly elicit excessive ranges of EDE-like antibodies and thus higher shield towards dengue.

Puneet Kumar is a clinician, Kumar Youngster Clinic, New Delhi. Vipin M. Vashishtha is director and paediatrician, Mangla Hospital and Analysis Heart, Bijnor.

Revealed – August 12, 2025 05:30 am IST