The spread of Aedes aegypti mosquitoes through the slave trade and later through the movement of ships and goods during the Second World War facilitated the global expansion of dengue virus. The first descriptions of dengue fever characterized the eighteenth-century pandemic of dengue infection as described in 1780 by Benjamin Rush during a large outbreak of dengue fever in Philadelphia, Pennsylvania, in the USA. Dengue was thought to have been introduced in the USA as a consequence of the rum and slave trade between Africa and Caribbean ports. Dengue outbreaks occurred throughout the USA, the Caribbean and South America during the nineteenth and early twentieth centuries. The second dengue pandemic was centred in the mining towns of northern Queensland, Australia, where boom towns and resulting Aedes aegypti population growth resulted in continuous dengue transmission from the 1870s until the First World War. Dengue outbreaks were also occurring in the Eastern Mediterranean and resulted in a large epidemic in Greece during 1928. During the Second World War, dengue strains were carried by ships and soldiers from South-East Asia to Japan, the Pacific Islands, Philippines and Hawaii. A new manifestation of severe dengue illness resulted, dengue haemorrhagic fever, first reported in the Philippines then later in Thailand during the 1950s.

The discovery of the role of Aedes aegypti in the transmission and spread of yellow fever and the subsequent isolation of the virus and creation of an effective yellow fever vaccine introduced the concept of mosquito control as an effective measure to disrupt yellow fever transmission. Subsequently the International Health Board and the Rockefeller Foundation instituted mosquito control strategies including the use of a larvicidal, Paris Green, throughout the USA and Central and South America. These techniques were soon applied to malaria control and during the years from 1924 to 1925, funding for malaria prevention through the strategy of mosquito control doubled. The success of this programme in Italy during the 1920s set the stage for the global use of mosquito control in the prevention of malaria. The Second World War prompted the creation of the Rockefeller Foundation Health Commission in 1942 to support national defence and in particular malaria control for U.S. forces. The need for lousicides to combat typhus ushered in a new insecticide developed by the Swiss firm, Geigy, called dichlorodiphenyl-trichloroethane (DDT). Led by Fred Soper, the Rockefeller team demonstrated the effectiveness of DDT as a lousicide and in disrupting typhus epidemics. DDT was soon used in aerial and ground spraying for Allied Forces during a malaria outbreak in Italy and was found to be a highly effective larvicide with a long environmental persistence. DDT subsequently became a key component of the World Health Organization's global malaria eradication campaign in 1955. This campaign resulted in the elimination of both the malaria mosquito vector and Aedes aegypti throughout South America and the virtual elimination of malaria, yellow fever and dengue throughout the Americas. A reassessment of this global strategy by the WHO and the growing concerns of the environmental effects of DDT led to the end of the use of DDT as a mosquito control larvicide in 1969. The cessation of DDT-based mosquito control programmes in the Americas and the social disruption that resulted from the Second World War allowed the spread of DENV in Asia, the reintroduction and resurgence of Aedes aegypti throughout the Americas and, consequently, resurgence of DENV, particularly South-East Asian strains, in the Americas.

The first two dengue pandemics were characterized by epidemics that produced severe outbreaks of fever, headache and myalgias, a clinical syndrome termed dengue fever. As waves of DENV-1 to -4 spread throughout the human population, especially in Asia, DENV adapted to be able to reach virus levels during a course of infection that allowed mosquitoes to become infected, thereby ensuring continued transmission of the virus. There is variation among vector species in their susceptibility to dengue and the potential selective effects of such variation on viral replication; however, high levels of co-circulation among serotypes also posed a challenge for the persistence of each serotype. Consider a DENV-2 strain entering a population that had a high degree of pre-existing antibody to an established DENV, such as DENV-1. Preexisting DENV-1 antibody, though not neutralizing, would under ordinary circumstances have provided significant heterotypic neutralization of DENV-2, potentially reducing viral levels in infected humans and thereby interrupting mosquito transmission. Thus, the presence of high levels of infection by multiple serotypes imposed significant selection for viruses that, via mutations in the E protein coat and changes in specific epitopes, were able to either fully escape the effects of heterotypic neutralization, or as is currently thought to be the case, to utilize these subneutralizing antibodies to enhance infection. This phenomenon of viral replicative enhancement due to subneutralizing heterotypic antibody is known as antibody-dependant enhancement (ADE). Since ADE results in higher viral loads, viruses with a particularly high tendency towards enhancement should have a selective advantage.

The ability of all DENV serotypes to utilize pre-existing heterotypic flavivirus antibody to enhance infection is a unique feature of DENV that is particularly common among South-East Asian strains. The tendency to be enhanced by heteroserotypic antibody distinguishes DENV from all other flaviviruses, and is the primary basis of DENV pathogenesis in severe dengue illness. During the third pandemic, this tendency of DENV to be enhanced in secondary dengue infection resulted in the clinical manifestation of a previously unrecognized sequelae of DENV infection - severe haemorrhagic disease and plasma leakage. First described as Philippine and Bangkok haemorrhagic fever during the 1950s, it is now recognized as dengue haemorrhagic fever (DHF).

from Endy et al. in Frontiers in Dengue Virus Research

Labels: Aedes aegypti, Dengue pandemics, dengue virus, Dichlorodiphenyl-trichloroethane, Haemorrhagic fever