Abstract & Commentary
Synopsis: A clinical trial involving school-aged children in Thailand shows that a tetravalent dengue vaccine is safe and immunogenic, despite frequently bothersome side effects.
Source: Sabchareon A, et al. Safety and immunogenicity of a three-dose regimen of two tetravalent live-attenuated dengue vaccines in five- to twelve-year-old Thai children. Pediatr Infect Dis J.2004;23:99-109.
Healthy flavivirus-seronegative children aged 5-12 years received 3 sequential doses of 1 of 2 candidate dengue vaccines or, as a control, rabies vaccine. Moderate reactions including fever, rash, headache, and myalgia were common with the first dose (seen in more than 80% of recipients) but decreased with subsequent vaccine doses. Serious adverse events did not occur, but one child had a weeklong dengue-like illness. Seroconversion rates were high (89% with one vaccine formulation; 100% with the other).
Comment by Philip R. Fischer, MD, DTM&H
Dengue fever is an important disease. It is estimated that 2.5 billion people in more than 100 countries live at risk of acquiring dengue.1 Cases and outbreaks occur in warm regions of Africa, Asia, Australia, the Pacific Islands, the Caribbean, and the Americas. In Southeast Asia alone, there are more than a million clinical cases of dengue reported each year.2 Already this year, there have been reports of increased dengue activity in Venezuela, El Salvador, the Seychelles, and Indonesia.3 Dengue poses a significant concern to international travelers, who currently must limit their protective efforts to mosquito avoidance measures.
Along with yellow fever virus and Japanese encephalitis virus, the dengue virus is a member of the Flavivirus genus. There are 4 different virus serotypes, and it is possible for humans to be infected concurrently or sequentially by multiple serotypes. The virus is transmitted by mosquitoes, primarily by Aedes aegypti.4 In endemic areas, school-aged children are at greatest risk of becoming sick with dengue fever.
About three-fourths of dengue infections are asymptomatic.2 About 94% of clinical cases present with just dengue fever.2 This is characterized by fever, headache, vomiting, and severe skeletal pain ("break bone fever"). A maculopapular rash spreads from the trunk to the limbs and face. Fevers can recur, along with lymphadenopathy, as the entire illness fades during its 1 - 1.5 week duration.4 Approximately 6% of clinically symptomatic cases of dengue manifest as severe illness — either hemorrhagic fever or shock — with potentially high rates of mortality. The diagnosis is usually made clinically, but antibody tests and antigen detection tests are done in some centers. No specific treatment is available, and supportive care is essential.
In a 2-year review of hospitalized Cambodian children, 80% of nearly 600 children with hemorrhagic fever had dengue. In fact, up to 10% of admissions to the hospital were related to dengue at some time.5 With no specific treatment available, preventive efforts are vital in combating the toll of dengue fever. Still awaiting a useful vaccine, mosquito control measures are critical.6
Dengue is widely recognized as a major problem in endemic areas, especially southeast Asia. Professionals and policymakers are interested in preventing dengue fever, and there is evidence of public perception that a vaccine is needed.7 Could a vaccine be cost effective? A careful, cost-effectiveness study was recently reported.2 Focusing on the needs in 10 Southeast Asian nations (population 529 million, with 1.2 million cases of dengue reported annually), and expecting that 2 vaccine doses would be needed (whereas 3 doses were used in the study summarized above to achieve protectively high antibody levels against each of the 4 dengue serotypes), vaccine was found to be extremely cost-effective (only $50 per disability-associated life year saved, similar or better than the cost-effectiveness for preventing polio, measles, and tetanus).
One of the concerns about dengue fever is that the life-threatening hemorrhagic and shock forms of the illness seem to be most likely with subsequent, rather than primary, dengue infections. An initial infection seems to "prime" the host defenses to make severe illness more likely in the future. A concern with vaccination is that vaccine might similarly pre-dispose recipients to more severe disease if/when they are subsequently exposed to another dengue serotype. The experience reported in the Thai study is encouraging in this regard. The side effects of vaccine were less bothersome after subsequent doses, suggesting that "priming" is not occurring. And, the 5 children who developed wild-type dengue after the initial vaccination, but before achieving full protection did not show any evidence of more severe, enhanced disease. Additional, larger studies will be needed, but current evidence suggests that disease enhancement is not a major problem with the current candidate dengue vaccines.
Thus, dengue fever is widespread in the world, devastating to millions, and rampaging without effective, specific treatment or implementable prevention strategies. The public desires vaccination in endemic areas, and current projections suggest that a vaccine could indeed be cost-effective. Thus, the study by Sabchareon and colleagues is timely and important. Dengue vaccine seems to be within reach. To be practically useful for travelers, however, briefer vaccination courses would be helpful, and vaccines with much lower rates of bothersome side effects would be desirable. Nonetheless, the current paper reminds us that progress continues, and a useful dengue vaccine for travelers might one day be in sight.
1. da Fonseca BA, Fonseca SN. Dengue virus infections. Curr Opin Pediatr.2002;14:67-71.
2. Shepard DS, et al. Cost-effectiveness of a pediatric dengue vaccine. Vaccine.2004;22:1275-1280.
3. Dengue/DHF Update 2004. ProMED mail post April 18, 2004.www.kpromedmail.org
4. Zuckerman AJ. Virus infections. In, Zuckerman JN, ed, Principles and Practice of Travel Medicine. John Wiley & Sons, New York, 2001, p 67-68.
5. Chhour YM, et al. Hospital-based diagnosis of hemorrhagic fever, encephalitis, and hepatitis in Cambodian children. Emerg Infect Dis.2002;8:485-489.
6. Guzman MG, Kouri G. Dengue: An update. Lancet Infect Dis.2002;2:33-42.
7. DeRoeck D, et al. Policymakers’ views on dengue fever / dengue hemorrhagic fever and the need for dengue vaccines in 4 Southeast Asian countries. Vaccine. 2003;22:121-129.
Philip R. Fischer, MD, DTM&H, Professor of Pediatrics, Department of Pediatric & Adolescent Medicine, mayo Clinic, Rochester, NM, is Associate Editor of Travel Medicine Advisor.