Published byAnnette Gerritsen
Published on25 April 2017
Article by Cameron Nutt and Patrick Adams published in The Lancet.
In April of 2016, reports were streaming in of Zika cases across the Americas: Panama, Martinique, Chile, and Peru. Just as officials had predicted, the epidemic was spreading fast. Each report reinforced the conventional wisdom that Zika was primarily a threat to the western hemisphere and that, so far, mainland Africa had been spared its pernicious effects. Then came a report from Guinea-Bissau.
According to the country’s Ministry of Health, from April to June, 2016, six infants in the small west African nation had been born with microcephaly after possible exposure to Zika. Clusters of suspected infection in adults were also reported across the country. Similar reports from South America had prompted swift responses from international health agencies, but it would be 3 months before blood samples from the infants in Guinea-Bissau were sent to an international laboratory and more delays followed.
Not until September, 2016, did the public learn that the adult cases were confirmed to have been caused by a local African strain of the virus, not one imported from Latin America. In November, diagnostic testing indicated three of the newborn babies had been exposed to either Zika or chikungunya, though further studies were ordered to differentiate between antibodies to the two viruses.
“In Guinea-Bissau, the surveillance system has detected a number of microcephaly cases which appear to be above the national baseline”, said WHO spokeswoman Monika Gehner. “With the support of foreign reference laboratories, Guinea-Bissau is diligently investigating cases of congenital malformations to determine whether the suspected microcephaly cases are caused by Zika virus infection in utero.” A year after the first report from Guinea-Bissau, those investigations have yet to produce results.
The delay itself is telling: a measure of the degree to which key assumptions have shaped the global response to this Public Health Emergency of International Concern. One such assumption is that the absence of evidence of congenital Zika syndrome in Africa constitutes evidence of its absence. There is also the widespread but unproven assertion that genetic differences between strains were primarily responsible for the ability of the virus to damage the CNS. Media outlets widely printed this as fact, yet a growing body of evidence has challenged these claims.
Evidence is accumulating
To date, at least 30 laboratory-based studies have suggested that African strains of Zika are capable of causing the same, or worse, damage to cells in the CNS, and reproductive and immune systems as the so called Asian lineage strains circulating in the Americas.
Many of these discoveries have occurred incidentally. Research teams were unable to obtain Zika samples from Brazil in 2015 and had to work with the original strain collected in Uganda in 1947. It was based in part on studies of this 70-year-old isolate, known as MR766, that international health authorities first concluded that Zika infection during early pregnancy is causally linked to microcephaly. “Using MR766 was not our choice”, said Hongjun Song, a neuroscientist at Johns Hopkins University, MD, USA, who, together with Guo-Li Ming, published the first paper to show the ability of the virus to infect and kill human neural progenitor cells. “It was simply the only strain available to us at the time of our study”, Song said.
Few scientists chose to highlight this fact or to discuss its implications for populations in Africa; some papers only identified the strain used in technical appendices. But as Song’s and Ming’s findings are replicated in laboratories around the world, they have become increasingly difficult to ignore.
One recent study by virologists at the French National Institute of Health and Medical Research showed that a strain of Zika from the Central African Republic is more than twice as deadly to human neural stem cells as the variant circulating in Latin America. “Unexpectedly, we found stronger virulence for the African strain”, said Sara Salinas, the study’s senior author. “We reproducibly detected higher rates of infection, viral reproduction, cell death, and antiviral responses with the African strain.” Later comparative studies in mice reported similar trends. “Many key questions remain about understanding the differences between African and Asian Zika strains”, said Darci Smith, a virologist at the US Army Medical Research Institute of Infectious Diseases, MD, USA, who led one of these studies, “but in general we believe strains of both lineages are equally concerning from a public health perspective”.
An invisible epidemic
Scientists now know that Zika is asymptomatic in up to 80% of those infected, and that only a small fraction of infections during pregnancy result in microcephaly. A wide spectrum of more insidious neurological sequelae is just starting to be defined. But before May, 2015, health officials had little reason to be concerned; what weak health systems could not detect, epidemiologists and scientists could not see, much less study.
“It’s one of those things where sometimes we don’t realise there’s a problem, so we don’t know to look for it”, said Ann Powers, acting chief of the arboviral diseases branch at the US Centers for Disease Control and Prevention (CDC). “Until we know there’s a problem, there usually isn’t funding for it.”
Zika has probably been circulating in nature in a sylvatic cycle for many decades, spilling undetected into human populations across Africa with unknown regularity, according to Powers. Indeed, studies have claimed to show widespread human exposure to Zika in at least 25 countries across the continent, and scientists recently reported definitive evidence that Zika has been continuously circulating across west Africa for decades. On analysing 387 frozen blood samples taken from febrile patients in Senegal and Nigeria between 1992 and 2016, 6·2% were positive for IgM antibodies to Zika virus. “We were a bit surprised by how much we found”, said Phyllis Kanki, a virologist form Harvard University, MA, USA, and the study’s senior author.
Four patients in the study also showed infection with an African Zika virus strain by real-time PCR. “It certainly is possible that there is a level of ongoing Zika virus infection in sub-Saharan Africa that is associated with microcephaly in fetuses of women infected during pregnancy”, said Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases. However, he said, the region could be “well past the outbreak stage and now has a low level of endemic infection that may result in some cases of microcephaly”.
In February, 2017, two studies suggested another potential explanation for the lack of observed birth defects associated with Zika in Africa. A research group at the University of Missouri, USA, reported that human trophoblasts making up the early placenta are killed much more rapidly by a Ugandan Zika isolate than by a Cambodian one. “This virus is so destructive of placental cells that pregnancy loss may be occurring very early on”, said coauthor and obstetrician Danny Schust. “If so, women may not even realise they were pregnant.”
A team of immunologists and obstetricians at Johns Hopkins have extended these findings to mice. Alongside Zika isolates from across Latin America and southeast Asia, they infected immunocompetent pregnant mice with a strain collected in Nigeria in 1968 and found “no significant differences in relative viral load, transmission rate, or fetal outcome”. Each strain tested was able to cross the placenta, and to result in either spontaneous abortion or neuroinflammation and cortical thinning of neonatal mouse brains.
“This all could have been going on for 100 years for all we know, and we just didn’t notice it”, said Michael Wells, a Harvard neurobiologist, who with his colleague Max Sallick showed that the Ugandan strain can infect primitive brain structures with effects that are nearly indistinguishable from those caused by the Asian lineage strain. There is a critical need for sensitive and specific diagnostics to do proper surveillance.
Microbiology and macroeconomics
The discovery that Zika was causing birth defects in the Americas might have prompted investigations on the continent where the virus originated. But this wasn’t the case.
In September, 2016, the US Congress allocated $1·1 billion for a domestic response to Zika, partly by re-appropriating $109 million previously set aside to enhance surveillance of infectious disease in west Africa after the region’s Ebola epidemic. The $2 million specifically dedicated by the African Development Bank to Zika surveillance across all of Africa pale in comparison. In light of the circumstantial evidence collected by bench scientists, said Fauci, one thing is clear: “There is a critical need for sensitive and specific diagnostics to do proper surveillance and epidemiologic fact-finding regarding Zika in sub-Saharan Africa”. According to Powers, early efforts are underway.
Less clear, however, is whether this nascent work can survive the acts of a US leadership unconvinced of the need for any surveillance. President Trump’s administration has ended US contributions to the UN Population Fund, which supports reproductive health care for women across Africa, and proposed eliminating the US Agency for International Development’s Global Health Security programmes, which help African ministries of health detect outbreaks of pathogens like Zika and prevent them from becoming pandemics.
Writing from Uganda in 1952, Zika co-discoverer George Dick observed that the “absence of the recognition of a disease in humans caused by Zika virus does not necessarily mean that the disease is either rare or unimportant”. It was a prescient insight.