Dengue still retains its deadly bite

Published in The Hindu on September 11, 2012

Aedes aegypti

The overall efficacy of the vaccine was “lower than expected” and was “not significant.” – Photo: Wikimedia Commons

The just concluded Phase IIb (proof-of-concept) dengue vaccine trial against all the four virus types (serotypes) that cause dengue has not only shown an unexpectedly low efficacy of 30.2 per cent but has also challenged many well-established hypotheses and ideas.

The trial was conducted in about 4,000 children in the age group 4 and 11 in the dengue endemic district of Muang in Thailand. The vaccine group had 2,669 children and the control group had 1,333 children. Primary analysis was conducted using data from 3,673 children.

The overall efficacy of the vaccine was “lower than expected” and was “not significant,” reported the authors of a study published in The Lancet on Tuesday (September 11). The low overall efficacy of 30.2 per cent “comes as a surprise,” writes Scott B. Halstead, a U.S-based senior scientific adviser for the Dengue Vaccine Initiative in a Comment piece accompanying the paper.

Protection against serotypes

The vaccine produced immune responses against all the four virus types. However, the vaccine only protected against three serotypes — type 1, type 3 and type 4 at a “range consistent with our assumed overall efficacy of 70 per cent after three injections,” they write.

“The lack of efficacy against serotype 2, and the fact that serotype 2 was the prevalent serotype during the study, diminished the overall vaccine efficacy caused by any serotype (statistical power limitation),” notes Derek Wallace, the Corresponding author of the study in an email sent to The Hindu . “The ongoing Phase III studies with over 31,000 volunteers will help further document efficacy in broader population and different epidemiological environments.”

For instance, children in the vaccine group had more number of dengue infections caused by virus type 2 than the control group. Twenty-eight days after the three injections, the vaccine group had 31 dengue episodes caused by serotype 2, while the control group had only 17. Similarly, after two injections, it was 44 cases in the vaccine group compared with 22 in the control group. The number of dengue episodes in the vaccine group after one injection was 52 compared with 27 in the control group.

Even in the case of serotype 1, the protective effect of the vaccine was a little lower than for virus types 3 and 4.

It is interesting to note that the vaccine produced “satisfactory” immune response (immunogenicity) against all the four serotypes. Yet, it did not offer any protection against serotype 2. “The observed lack of efficacy against DENV2 despite satisfactory immunogenicity is surprising and will need further investigation,” they write.

What it challenges

The authors also question the “robustness” of the “assumption” that a dengue vaccine should induce “balanced immunogenicity” against all the four serotypes to keep dengue infections at bay.

The trial result “challenges vaccine development hypothesis” on the grounds that “similar levels of protection against all the four serotypes” should be seen when neutralising antibodies have been induced for all four virus types.

Natural dengue infection by any serotype produces lifelong immunity against that serotype. Though infections caused by all the four serotypes are common in the dengue endemic study area, those caused by serotype 1 and then type 2 are predominant.

However, the number of dengue episodes caused by type 2 and type 1 is more than the other two types in both the vaccine and control groups after one, two and three injections respectively. Moreover, the number of dengue episodes caused by virus type 2 is more in the vaccine group than the control group at all stages of the trial.

Infections by two or more dengue virus types should have produced “broad neutralising antibody response” against dengue diseases caused by any of the virus types, notes Dr. Halstead. But that has not been the case, though.

Dr. Halstead suspects that the trial might have failed to obtain a “balanced immune response” when a cocktail containing all four virus types was given to children living in an endemic area. He finally concludes by writing that “serious deficits remain in our understanding of the mechanism or mechanisms by which human beings are protected against initial and successive infections” with four virus types.

So should “type-specific antibodies” be given to prevent the occurrence of dengue diseases? “The four serotypes are circulating across the world, and several serotypes can coexist in the same region. Our goal is to provide the broadest protection possible for individuals living in endemic areas as well as for individuals who plan to travel to those areas,” Dr. Wallace notes in his email. Though the trial has not been able to achieve its primary objective, it has been successful on other fronts. The vaccine proved to be safe and well tolerated in all the vaccinated children. The scientists have been able to develop an efficacious dengue vaccine by overcoming a big challenge — no animal models exist for testing efficacy. Also, dengue is caused by four different related viruses, thus complicating the development of an efficacious vaccine.