Public health

Zika control, the Ugandan way

Print edition : November 25, 2016

The Zika virus was first identified, in 1947, in the blood sample of a rhesus monkey in the Zika forest of Uganda. The forest, now owned by the Uganda Virus Research Institute, has for decades been at the centre of a massive project to study viruses and the mosquitoes that carry them. Here, a caretaker and tour guide posing in the forest. Photo: Stephen Wandera/AP

Angelica Pereira with her daughter, Luiza, who was born with microcephaly because of the Zika virus, and her husband at their home in Santa Cruz do Capibaribe, Pernambuco State, Brazil. A December 23, 2015, photograph. Photo: Felipe Dana/AP

A pest control worker fumigating drains and gardens at a housing estate in Singapore where Zika infections were reported from, in September 2016. Photo: Wong Maye-E/AP

Thailand confirmed two cases of microcephaly caused by the Zika virus in September 2016. Here, a city worker fumigating the area in Bangkok from where the cases were reported. Photo: Athit Perawongmetha /Reuters

Uganda’s success in containing the Zika outbreak is the product of a long history of cutting-edge infectious disease research that resulted in the discovery of dozens of diseases and the establishment of a virus surveillance system to curb potential epidemics.

MANY vector-borne viral diseases are zoonoses, that is, they have cycles involving animals other than humans: for instance, yellow fever, West Nile, St. Louis, Eastern equine encephalitis and Kyasanur Forest disease (KFD), which have primates, bats, small mammals or birds as reservoirs or intermediate hosts or amplifiers. Zoonotic transmission cycles are more complex. Often, additional vector species with catholic blood-feeding habitats are necessary to transmit pathogens acquired from animal hosts to humans, as in Kyasanur Forest Disease. When humans and domestic animals enter rural or sylvan foci, or when the vectors disperse into residential areas, there is a public health problem. There thus exists a complex host-parasite relationship among humans, various animals, their arthropod vectors and infective organisms, with environmental aspects having a major impact.

The most recent example that has come to our notice is the Zika virus, which has created a stir (or fear) in the Americas, particularly Brazil. Information about the virus has been available for 70 years, but it was never considered a public health problem. It occurred throughout Asia and Africa, but the occurrence was sporadic and there was never any severe disease associated with it. The virus was isolated for the first time in Uganda in 1947 from a sentinel monkey and later from Aedes africanus mosquitoes. There are also reports of isolations from Aedes aegypti, a known vector of dengue, chikungunya and yellow fever.

The Zika virus, a group B arbovirus (flavivirus), has cross reaction with other flavivirus antibodies, for instance with dengue, West Nile and yellow fever. Zika antibodies have been found in several West African countries and now in Brazil and many other South and Central American countries. The virus is transmitted by the day-biting mosquito Aedes aegypti. Actually, evidence of the presence of the Zika virus in India was available as early as the 1950s. The Rockefeller Foundation did the first ever serological survey in India in 1949-50. The study was conducted by K.C. Smithburn of the Rockefeller Foundation, J.A. Kerr, director of what was then the Virus Research Centre, and P.B. Gatne, Medical Officer of the Bombay State. The findings of their study were published in 1954. They had collected blood samples from indigenous residents from several States and tested them for neutralising antibody against each of 15 different viruses known or believed to be arthropod-borne. All tests with yellow fever, Bwamba fever, and Bunyamwera viruses were negative. But significant numbers of the sera neutralised Zika. There is, however no record, as yet, of the isolation of the Zika virus from the Indian subcontinent.

Public health threat

Has the Zika virus been looked at seriously enough in India? Already dengue and chikungunya are major public health problems and their effective control is beset with difficulties. It is only a matter of time before Zika also becomes one.

As already stated, there is animal involvement in the natural cycle of many viruses. For instance, wild birds are involved in the spread of Western equine encephalitis (WEE); Ardeid birds in the case of Japanese encephalitis; many animals and birds, including primates, in the case of KFD; wild monkeys in the case of yellow fever. In the case of dengue, bats have been shown to be involved; the chikungunya virus was isolated from Aedes africanus collected from African forests. In all these cases, some of the arthropod vectors are common and some are different.

Since these are zoonotic diseases, some mammals may be definitive hosts in some cases and in some others they may be intermediate hosts. Many small mammals, which have large populations, may harbour the virus, infecting their ectoparasites, and also play the role of reservoirs of the virus in nature.

Some animals may be amplifiers of the virus; some others, like cattle, may be multipliers of the vector population. It is thus a complex biocoenotic relationship that exists between the infective agents and various non-human hosts and vectors in the forest ecosystem. Humans, of course, are the ultimate victims.

The epidemiological pictures vary in the case of different viruses. In the spread of the Zika virus, monkeys, the forest environment and the yellow fever mosquito Aedes aegypti are all involved, and so it is essential to know more about its natural cycle.

In a recent study, scientists of the Oswaldo Cruz Foundation in Brazil were able to infect another common mosquito species, Culex quinquefasciatus, with the Zika virus in the laboratory, raising concerns that the virus could be carried by a species more prevalent than Aedes aegypti.

It has been well documented that there are, epidemiologically speaking, three different cycles of yellow fever. In the “urban cycle”, only Aedes aegypti is involved. It is well adapted to urban areas and can also transmit other diseases, including dengue fever and chikungunya. There is a “sylvatic cycle” (forest cycle or jungle cycle) in Africa and South America, in which Aedes africanus (in Africa) or mosquitoes of the genus Haemogogus and Sabethes (in South America) serve as vectors. In the jungle, mosquitoes infect mainly non-human primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way in which humans can infect each other, which explains the low incidence of yellow fever cases.

People who become infected in the jungle can carry the virus to urban areas, with Aedes aegypti acting as the vector. Yellow fever could not be eradicated because of the sylvatic cycle. In Africa, a third infectious cycle known as the “savannah cycle” or the intermediate cycle occurs between the jungle and urban cycles. Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa.

The sylvan cycles of the disease caused by the Zika virus and also of dengue should be investigated; these have close similarities with yellow fever. There have been no studies on this in India. This virus continues to circulate in the forests. In the past 10 years, a number of dengue outbreaks have taken place. At least two factors contribute to the re-emergence of dengue: rapid human population growth near tropical forests and the fact that sylvatic dengue has been shown to adapt to human hosts and urban mosquitoes. The problem has become acute in areas bordering forests, such as Kottayam in Kerala. There is little or no adaptive barrier to the emergence of sylvatic dengue in human populations. The virus can emerge from its current environment at any time. With the exception of research programmes in Malaysia and Sri Lanka, work on sylvatic dengue has been minimal. It is said that of all the viruses with the potential to shift from animals into humans, the most likely to do so are those that, like sylvatic dengue, are carried by non-human primates and/or bats.

Bats as reservoirs

Bats evolved long before humans in the early Eocene period. The flying fox, Pteropus sp., which is implicated in the natural cycle of dengue in Australia, is also commonly found in India. The KFD virus was found circulating in a closed colony of an insectivorous bat ( Rhinolophus rouxi) in a disused well in Shimoga district of Karnataka. These bats were found infested with a soft tick, Ornothodoros. The KFD virus was also isolated from these ticks. This indicates that the viruses had existed in a closed cycle for ages. Some of the planet’s scariest and most lethal viruses such as the Ebola and rabies find a natural refuge in bats. Many major epidemics have been traced to bats, and scientists are discovering new bat-borne viruses all the time. Linfa Wang of Australian Animal Health Laboratory said the role of bats was too important to be ignored anymore. Bats and other animals such as rats and mice that chronically harbour viruses are important as disease reservoirs.

The animals acting as reservoirs, however, rarely show symptoms of the disease. But sometimes the viruses they carry infect new, more vulnerable species. Scientists at Australian Animal Health Laboratory suspect that bats are to blame for the start of epidemics. Dengue is thus the most rapidly emerging disease in the tropics. A serologic survey carried out in Sri Lanka indicated that an epizootic dengue virus was active among macaques. A single epizootic dengue outbreak took place between October 1986 and February 1987, during which 94 per cent of the macaques within the study site were affected.

Uganda model

When one considers the investigative research on the zoonotic origin of these diseases, the work of the Ugandan Virus Research Institute (UVRI) is worth emulating. Uganda’s success in containing Zika outbreaks is no accident. It is the product of a long history of cutting-edge infectious disease research, dating back to the founding of the UVRI, to stem the spread of yellow fever in East Africa. The institute passed into the hands of the East African Community in 1950 and then over to the Ugandan Ministry of Health in 1977.

Scientists there have discovered dozens of diseases and pioneered a viral surveillance system that has played a critical role in curbing potential epidemics. The UVRI has shown that crisis management of the sort advocated by the World Health Organisation (WHO) is a poor replacement for vigilantly monitoring for potential public health crises in the first place and aggressively containing them once they arise. “Ebola came; they react. When Zika came, there was a reaction,” said Ernest Tambo, an epidemiologist who has worked throughout Africa.

Another way of posing that question is, When will the world (including India) catch up with Uganda? “Uganda is a biodiversity hotspot,” said Julius Lutwama, the UVRI’s senior principal research officer. “We have wide flora, wide fauna, and, of course, the good temperature, the good climate. And what is good for humans, what is good for animals, of course, is also good for viruses.” The presence in the country of so many of the world’s most virulent pathogens has compelled it to become a world leader in virus surveillance. Martha Kaddumukasa, an entomologist at Uganda’s Makerere University, said: “They’re always monitoring the conditions, so that there’s no outbreak that they’re not aware of.” In 1952, the Rockefeller Foundation did pioneering work on arboviruses, leading to the discovery of Japanese encephalitis in India, and of KFD. It had isolated many viruses from arthropod vectors from different parts of India. For some of these isolates, matching human diseases were found only much later (for instance, the Ganjam virus).

The first major study in India in a virgin evergreen forest was also done by the Foundation in 1954. It was unique in every way since all components of the ecosystem were studied in Devimane Ghat in North Kanara (now Uttara Kannada) district of Karnataka State: a virgin, tropical, evergreen forest, with high rainfall, similar to the deep jungles of Africa and South America where yellow fever was prevalent. The comprehensive programme looked at virological, serological, entomological and ecological aspects of arboviruses. It was conducted for over a year before it was abruptly terminated.

Not much is known about the results of these investigations; but such extensive studies should be conducted again in a virgin forest ecosystem for an understanding of the zoonotic aspects of the viruses. Many questions should be asked about the inter-epidemic cycle of dengue and chikungunya viruses and the possibility of a zoonotic cycle. The excellent studies conducted in Malaysia and Sri Lanka were models that should be followed. There should be long-term, problem-oriented, multidisciplinary investigations in the field, particularly in dense jungles and their interfaces for knowledge of what is happening to these viruses in nature.

Jorge Boshell’s excellent exposition on the epidemiology and natural cycle of KFD, a product of more than a decade of intensive study in the Shimoga forests of Karnataka, can serve as a model to be followed in studies on new diseases such as the one caused by the Zika virus.

Need for research

A virus has got fantastic capabilities to survive; nothing but exhaustive research in the natural environment can unravel its mysteries. Two of the best known examples are studies on yellow fever and, of course, KFD in India. We have had stalwarts such as K.F. Meyer, Fred Soper and Bill Reeves and their adventurous work as examples to follow.

The threat posed by the Zika virus makes necessary an extensive viral surveillance system on a continued basis. There is a need for diagnostic facilities, ecological surveys and studies on all environmental (climate, vegetation and topography) aspects, the epidemiological aspects, the population dynamics of the human host and, most important of all, the vectors (actual and potential) involved and their potential to carry diseases and their distribution in space and time.

At present, the dengue epidemic is an annual feature in many cities in India. As recently as August 2016, scores of Zika virus cases were reported from Singapore and a yellow fever epidemic was reported from Angola.

It is time the country shook off its “All is well and we are in deep slumber” attitude. There is no need for any new or innovative methods to tackle the problem. Let the agencies responsible do their job more intensely, strengthen the surveillance mechanism and concentrate more on environmental sanitation.

Dr P.K. Rajagopalan is former Director, Vector Control Research Centre, Puducherry, an institute of the Indian Council of Medical Research.

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