Broadly neutralizing antibodies to dengue virus that recognize a repeated motif on the viral envelope might pave the way for a better vaccine, scientists reported this week.

The results, corresponding author Gavin Screaton of Imperial College London said, are the first proof of principle that one antigen can be used to immunize against all four serotypes of dengue, which is critical for the success of a vaccine because of the way the immune responses to those serotypes interact with one another.

Over the past 50 years, dengue virus infection has gone from being a relatively rare event to something that afflicts 400 million people annually in a growing fraction of the globe. The frequency of infection has increased “almost exponentially over the last 50 years.”

Historically, about a quarter of infections cause noticeable illness. Of those, the majority is relatively mild, but “a small number of infections cause much more severe disease and potentially dengue hemorrhagic fever,” Screaton said.

The fatality rate of severe infections can be up to 20 percent, though he noted it is usually lower if treated in hospital.

“The real problem with dengue,” he said, “is that it occurs in an epidemic fashion.” And as a result, the virus can paralyze health care systems when it comes to a big city.

And it’s not just the frequency of infection that has been occurring. Severe infections have been rising disproportionately.

The reason – which is also a major complication for the development of an effective disease – is that there are actually four types of dengue. And infection with one type does not protected against the others.

In fact, a previous infection may make matters worse, because it turns out that as with knowledge, a little immunity is a dangerous thing.

“If you are going to become very sick and develop dengue hemorrhagic fever, you are far more likely to do so when you are infected the second time,” Screaton said. “Something about the immune response to the first contact primes you for a worse outcome.”

The increase in severe infections may be due to the fact that modern life has led to greater overlap of the strains’ geographic range.

They have likely evolved in isolation, and “globalization, travel, urbanization has allowed them to actually mix . . . so you now get situations where all four are circulating in a single population,” Screaton said. “It’s a disease of urbanization.”

This need to make a vaccine strongly protective against all four strains of dengue is a major challenge to vaccine development. In two large-scale trials, the tetravalent vaccine CYD-TDV (Sanofi Pasteur, the vaccines unit of Paris-based Sanofi SA) has given some protection against infection overall. Sanofi Pasteur plans to file for approval of the vaccine in countries where dengue is a public health concern, and hopes for approval in 2015. (See BioWorld Today, Nov. 10, 2014.)

But CYD-TDV is less effective against dengue-2 than other serotypes, leading to the disconcerting possibility that the vaccine may increase the probability of severe infection if an individual is first vaccinated, and then infected with dengue-2.

In their study, Screaton and his colleagues collected blood from patients suffering from a dengue infection and looked at their antibodies with the goal of identifying broadly neutralizing antibodies that could protect against all four strains.

They succeeded, and have reported their findings in the Dec. 15, 2014, issue of Nature Immunology.

“We’ve found a new class of antibodies which make up nearly a third of antibodies” produced by those infected with the virus, Screaton said.

Intriguingly, those antibodies recognize a previously unidentified epitope that is made up of parts of two separate viral envelope proteins.

Dengue’s viral shell is made up of repeats of different proteins that Screaton described as “snapped together.”

“The antibody,” he added, “recognizes the junction between two of these proteins . . . it will only recognize the protein when it’s part of the virus.”

Antibodies recognizing this particular epitope were able to neutralize all four strains of dengue virus – the first time such a broadly neutralizing antibody has been identified.

“It hasn’t really been realized until now that fully cross-reactive antibodies against dengue can be made,” Screaton said. “So the vaccine strategies which have been used to date generally involve trying to immunize people against all four strains of dengue virus individually.”

The work, it is hoped, could pave the way to a broadly effective vaccine.

Such a vaccine, he cautioned, “will take a considerable amount of time” – on the order of several years. But he said a vaccine will be critical to success in the fight against dengue.

Antivirals are challenging to develop because the infection progresses very rapidly. And efforts to control the mosquitoes that spread the infection – both classical public health measures and efforts at birth control – have their own challenges. (See BioWorld Today, Aug. 25, 2011.)