One year into the Zika outbreak: how an obscure disease became a global health emergency

The burning question: are populations in Africa and Asia protected by immunity?

Although the re-profiling of Zika from a benign disease to a global health emergency stimulated a flurry of research, the disease remains poorly understood at levels ranging from its virology and epidemiology to the clinical spectrum of complications it can cause. No one can answer questions about further international spread with certainty, though theories abound.

As the virus has been detected in parts of Asia and Africa for several decades, some level of endemicity is assumed, though no one knows whether presence of the virus over time has resulted in widespread or low-level immune protection or possibly no protection at all.

In Africa, the ancestral transmission pattern is a sylvatic cycle, involving mosquitoes in forest canopies that preferentially feed on monkeys. This pattern may have historically restricted human cases to very small numbers, or cases may simply have been missed during low levels of “silent” transmission. The vast majority of Zika infections produce no symptoms at all. When symptoms do occur, they are mild and mimic those seen in dozens of other viral infections common in the tropics.

Moreover, microcephaly and Guillain-Barré syndrome are low-frequency events that are easily missed. In Asia and Africa, surveillance systems set up to detect polio-associated paralysis might pick up some cases of GBS, but this surveillance is geared towards detection in young children whereas GBS tends to affect older adults.

Other researchers, pointing to differences in the African and Asian lineages of the virus, note that the African lineage has never been known to cause an outbreak. The outbreak in Cabo Verde, which began in October 2015 and caused more than 7,000 cases, remains a puzzle. Sampling and transportation problems have delayed sequencing of the virus.

Health officials in Cabo Verde believe the virus might be of the Asia lineage, given the country’s strong travel ties with Brazil where viruses from the Asian lineage are circulating. As an alternative theory, viruses from both lineages may have circulated during the outbreak. Of note, no cases of Guillain-Barré syndrome have been detected despite dedicated surveillance; two cases of microcephaly have been confirmed.

Some experts speculate about what might happen if the recently emerged epidemic strains of the Asian lineage begin to spread in the sprawling cities of tropical Africa and Asia, with their dense populations of people and mosquitoes and flimsy infrastructures. Others believe that infection with viruses from one lineage might provide at least some protection against infection with viruses from the other, but no one knows for sure.

Still others use statistical vulnerability to assess the theoretical threat: more than half the world’s population lives in areas infested with Ae. aegypti. In any event, research is now rapidly filling in the gaps left during the many decades when Zika looked like a harmless disease, unworthy of much attention.

Evidence suggesting at least some level of immune protection comes from two sources: older surveys that detected Zika antibodies in blood samples and recent case reports of travellers infected with Zika while visiting a country with no documented ongoing virus transmission.

Numerous surveys, conducted in Africa and Asia in the 1950s and 1960s, detected Zika antibodies in blood samples. However, the results need to be interpreted with caution, as the researchers used different detection methods with varying degrees of specificity. As researchers themselves noted at the time, the finding of antibody to a given virus in a single blood sample from a donor is not conclusive proof of either infection or protective immunity.

Because of immunological cross-reactions among related viruses, studies thought to have detected Zika may have detected antibodies to dengue or another similar virus that co-circulates with Zika and is carried by the same mosquito species. The occurrence of Zika cases in countries is ideally confirmed by PCR testing or by virus isolation.

Additional anecdotal evidence comes from travellers from Zika-free countries, like Australia, Canada, Finland, Germany, Japan, and the United States, who acquired PCR-confirmed Zika infection after visiting countries in Asia and Africa that had not detected recent virus transmission in their territories and were unaware of a potential outbreak [table 2].

In this case, immunologically naive travellers may have acted as sentinels for the detection of virus circulation that might otherwise be missed, possibly because widespread immunological protection limits the number of cases. Alternatively, the mild self-limiting nature of Zika infection, the absence of symptoms in the majority of infections, clinical symptoms of Zika that overlap those of dengue and chikungunya, the weakness of surveillance systems, and the difficulty of differential diagnosis may mean that Zika infections occur in these countries but are not being detected.

Experts who advise WHO and have closely followed the dramatic resurgence of dengue and the recent transformation of chikungunya into an international threat are reluctant to issue reassuring advice concerning the potential of epidemic Zika virus strains to spread beyond the Americas. Outbreaks of dengue are now recurring in countries at short intervals, suggesting it is unlikely that Zika will simply burn itself out and go away. Moreover, flaviviruses are well-equipped to adapt to ecological pressures and exploit opportunities to spread.

The latest “firsts” for the Zika virus in the Americas are not encouraging in terms of virus persistence and the potential for further spread. In April 2016, researchers in Ecuador and the northeastern part of Brazil reported the detection of Zika in monkeys, suggesting a new transmission cycle that could allow the virus to persist. In Brazil, the virus detected in monkeys was identical to the one circulating in humans.

At the end of that same month, researchers at a government laboratory in Mexico reported detection of the Zika virus in female Aedes albopictus mosquitoes collected in the wild, as opposed to experimentally infected – another first for the western hemisphere. Ae. albopictus, also known as the Asian tiger mosquito, is an invasive species that continues to expand geographically well beyond Asia and has adapted to flourish in a variety of habitats closely associated with humans. As the mosquito can survive the winter in temperate climates, its ability to carry the Zika virus could expand the map of areas at risk of Zika virus transmission significantly.

Most likely, Zika – now re-profiled as a serious disease – is on the move, and this virus has staying power.