A vaccine against dengue has proved remarkably hard to develop. One reason is that the virus comes in four varieties known as serotypes.

In 18th century America, it came to be called “break bone fever,” a grim testament to the excruciating pain the sufferers experience. Dengue, according to the World Health Organisation, is the most rapidly spreading mosquito-borne viral disease in the world.

In the last five decades, the incidence has jumped 30-fold. The disease is now endemic in over 100 countries, placing two-fifths of the world's population at risk. Not only is the number of cases increasing as the disease spreads to new areas but explosive outbreaks are occurring, the global agency notes.

Globally, it is estimated that 50 million-100 million people become infected with the virus each year, and 5,00,000 of them — a very large proportion children — develop life-threatening forms of the disease.

Over the years, dengue has become endemic across much of India, says U.C. Chaturvedi, a virologist who has studied the disease for many years. Most people who become infected will recover without any problem. But to keep the death rate down, it is essential that signs of severe forms of the disease, such as a rash and small bleeding spots on the skin, be recognised. Such people must be immediately admitted to a hospital that can provide supportive treatment, he says.

Without proper treatment, death rates can approach 10-30 per cent, he notes. But mortality can be kept to less than one per cent with sufficient medical care. In the process, however, hospitals can become heavily burdened when a large number of people become infected during outbreaks, he adds.

‘Major health problem'

“The spread of dengue virus throughout the tropics represents a major, rapidly growing public health problem with an estimated 2.5 billion people at risk of dengue fever and the life-threatening disease, severe dengue,” observed Daniel P. Webster of the John Radcliffe Hospital in the U.K. and others in a review paper published in the Lancet Infectious Diseases in 2009. A safe and effective vaccine, they said, was urgently needed.

But while vaccines are available against yellow fever and Japanese encephalitis, caused by closely related viruses, a vaccine against dengue has proved remarkably hard to develop. Nevertheless, a number of different approaches to producing vaccines against it are being tested, from live but weakened viruses to killed viruses, and giving bits of viral protein. Some of these are already in clinical trials.

One hurdle to any prospective vaccine is that the virus comes in four varieties known as serotypes. A person who recovers after being infected with one serotype develops lifelong immunity only to that form of the virus, not the others.

The paradigm has been to make a vaccine that contains the four different viruses and get simultaneous immunisation against each of them, says Scott Halstead, a leading expert on dengue and vaccines against it. Dr. Halstead, who was born in Lucknow, is currently director of the Dengue Vaccine Initiative's Supportive Research and Development Programme.

It is possible to combine viruses from different families in a single vaccine as in the case of measles, mumps and rubella (MMR) vaccine. But with regard to the dengue vaccine, when the four different viruses are given together, there will be interference between some of the viruses that is unpredictable and quite erratic, he says.

Sanofi Pasteur, for instance, spent about 15 years working on a vaccine only to find that one virus out-competed the other three. It finally switched to a completely different vaccine type, he added. Others too had a similar experience. (The new type of dengue vaccine from Sanofi Pasteur, vaccine division of the French company Sanofi Aventis, is currently the most advanced in clinical trials. It could be ready for licensing as early as in 2014, according to a paper that appeared in the journal PLoS Medicine last month.)

Vaccines try to generate antibodies, mimicking the natural process by which people develop immunity after catching a disease. These antibodies then recognise and latch on to the germ if it gains entry into the body again and prevent it from setting up an infection. In dengue, however, there are concerns about antibodies themselves contributing to the severe disease.

Epidemiological studies carried out in Thailand in the 1960s showed that more than 85 per cent of severe dengue cases happened in people with pre-existing dengue antibodies, pointed out Dr. Webster and others in their review paper. Additional evidence from infants with maternal antibodies too lent weight to the hypothesis of immune involvement in the development of severe dengue.

Antibodies generated by the first dengue infection protect the person from being infected again with the same serotype. It turns out that if the next infection is caused by a different dengue virus, the antibodies can actually form a complex with it. Such complexes then bind to certain immune cells, leading to increased viral uptake and replication. The much greater number of viruses produced in the body then increases the severity of the disease. This process is known as antibody-dependent enhancement of infection.

‘Perversion of immune response'

“So we really have in dengue the most amazing perversion of the immune response,” remarked Dr. Halstead in an interview at the New York Academy of Sciences in 2009. The cells that were supposed to scout out and kill the viruses as well as the antibodies that were supposed to destroy them were forming “an unholy complex” to defeat the immune system.

However, Dr. Webster and his colleagues also pointed out that severe dengue could happen even with the very first infection. Moreover, only a small proportion of secondary infections progressed to severe dengue, suggesting that other factors too were involved. There was, they said, evidence of links between disease severity and nutritional status, ethnicity, virulence of the infecting strain and the host's genetic background.

“Whatever the role of antibody-dependent enhancement, it seems that a vaccine inducing a long-lived neutralising antibody response against all four serotypes simultaneously should not induce any risk in this respect,” they went on to note.

To avoid problems with under-vaccinating people, Sanofi Pasteur has adopted a conservative three-dose regimen for its vaccine, Dr. Halstead told this correspondent. A second dose after six months helped raise the antibodies in those who did not respond after the first dose. Even so, a third dose was still required to really get close to a 100 per cent antibody response to the vaccination.

But the challenge of developing a dengue vaccine may not end with successfully completing human trials and getting a licence for public use.

Trials will need to address the risk of persons acquiring or developing severe dengue as a direct consequence of vaccination, noted a summary of a WHO Technical Consultation published in the journal, Vaccine, in 2008. Long-term follow-up of those who participated in vaccine trials would be a powerful way of conforming or rejecting such a risk. Such follow-up should be planned in advance, it said.

‘Sustained, long-term follow up'

“Dengue vaccine, more than almost any other, is going to require sustained, long-term follow up,” agreed Dr. Halstead. On the one hand, real world experience with dengue indicated that it was only the first infection that sensitised people to a severe disease. On the other, if a person had two different dengue infections, he would essentially be no longer at risk. That means any booster vaccine that really takes effect should be protective, he added.

If a safe and effective vaccine becomes available, it would be possible to consider immunising children and young adults in parts of India where the disease is endemic, according to Dr. Chaturvedi. It is people in these age groups, rather than older adults, who are the most affected by severe forms of dengue and among whom most of the mortality occurs.

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