Background
The Zika virus (ZIKAV) was considered harmless until the Guillain-Barré syndrome and other autoimmune complications were shown to be associated with the infection during the French Polynesia outbreak in 2013–2014 [
1]. The 2015 Latin America and the Caribbean (LAC) outbreak increased its scientific and public health interest worldwide [
2]. Over one million people were infected in the region, with a shocking number of microcephaly cases in fetuses and infants [
3,
4]. Given the epidemic extension and the identification of ZIKAV as the causal link of congenital neurodevelopmental defects, the World Health Organization (WHO) recognized the ZIKAV infection as a public health emergency of international concern (PHEIC) [
5]. In 2017, it was estimated that the ZIKAV disease was responsible for 2.24 thousand disability-adjusted life years (DALY) globally [
6].
Despite significant advances, ZIKAV remains an enduring scientific and technological (S&T) health challenge. So far, the physiopathology and broad spectrum of clinical manifestations have not been completely understood. There is a lack of reliable diagnostic assays, and no vaccine or specific anti-viral treatment available. Though these technological advances are expected shortly [
7], ZIKAV is likely to have significant and long-lasting social and economic impacts across LAC [
8].
Previous bibliometric studies have shown that scientific publications on ZIKAV have greatly increased in the last few years [
9‐
12]. However, not much is known about the potential S&T contributions of LAC countries. It has been suggested that expanding the science, technology and innovation base in developing countries, as well as their insertion in research networks, would improve their response and preparedness to emerging health threats of global concern [
13]. An assessment of how LAC countries responded to the scientific challenge imposed by the ZIKAV outbreak can provide useful information to the global health community, and guide the prioritization of research and financial investments.
In this paper, ZIKAV-related publications and patents were reviewed to examine: i) LAC’s contribution to the worldwide scientific knowledge production and potential technological development; ii) research areas in which LAC countries mostly contributed; iii) role of LAC countries in the research network; iv) LAC patenting profile. This information is expected to contribute to the discussion of the role of S&T knowledge produced and disseminated regionally to address global health challenges.
Discussion
This study presents a comprehensive review of ZIKAV’s scientific knowledge production and potential technological development by combining the analyses of scientific publications, research networks, and patents. It gives an overview of the global S&T response to ZIKAV infection with special emphasis on LAC countries. The LAC region was the most affected area in the last outbreak and the region is expected to face the greatest public health impacts from ZIKAV disease. The analysis of regional contributions is relevant not only to inform future research and guide investments, but also to assess LAC countries’ potential role in tackling global health threats imposed by emerging diseases [
13,
20,
21].
Our analyses confirmed the poor interest in ZIKAV R&D prior to 2015 and the striking S&T response after the LAC epidemics when severe clinical complications were attributed to the infection. WHO’s appeal for the opening of data and research information on ZIKAV was probably among the factors that promoted such a rapid reaction from the scientific community. It directly influenced the scientific communication by encouraging journals to “fast track” ZIKAV-related publications [
22]. This increase in R&D activities was also bolstered by the funding made available by several international agencies [
23,
24].
A reliable assessment of the LAC region’s scientific contributions in any given area is usually hindered by the use of international databases as unique sources of information [
25,
26]. The impact of excluding regional databases is exacerbated by the trend of LAC authors to publish in regional and local journals due to languages barriers and costs of international journals [
25]. Our review showed that 70% of all ZIKAV publications indexed in LAC regional databases were also available in the international databases. This indicated that an eventual bias due to low representation of regional articles was potentially reduced in this study. It seems that the global importance given to ZIKAV along with the high incidence of cases in LAC countries urged that knowledge produced regionally was made noticeable globally. Such global interest might also have influenced editorial decisions of international journals [
9].
During an epidemic, the role played by countries in a knowledge-generating network is an important parameter for influencing response, decision-making, preparedness, and empowerment. Our analyses showed that scientific efforts from LAC countries, especially from Brazil, had a significant role in the generation of global knowledge on ZIKAV. Brazilian scientists were responsible for seminal work on outbreak characterization [
27,
28] and documented the high incidence of microcephaly and the association of ZIKAV infection during pregnancy to newborn malformations [
29‐
32].
The betweenness centrality analysis identified key countries acting as a “bridge” in the scientific community and suggested a prominent role for Brazil facilitating access to novel information and resources in the network. As a practical example of such role, when international scientists suggested that the 2016 Olympic Games should be put off Brazil because of the “Zika problem” [
33], it was a report from Brazilian scientists that brought epidemiological evidence that the epidemic was in decay, and there was no increased risk for disease transmission [
34].
In the patent analyses, Brazilian assignees were the single representatives of LAC countries. It should be kept in mind that, given the common delays in the publication of patent filings in the country, the number of patents may be underestimated. Although Brazil’s performance was less expressive than the USA and China, it still had an important position, ahead of patent leaders like South Korea, Germany, and Japan. Its leading position among LAC countries is in accordance with the results obtained in the assessment of scientific publications. Brazil’s small share of ZIKAV patents (5%) seems to be consistent with the publication’s profile, which focused mostly on the clinical manifestations of ZIKAV and vector control, areas that do not necessarily involve technological development. It has been argued that vector control is necessary as an immediate measure for epidemic control, but it should be undertaken in combination with other efforts such as the implementation of an R&D agenda and strengthening social programs and health systems [
35].
Brazil also stands out as the main country of protection for the patent families filed in national offices, a natural reflection of the 2015–2016 outbreak. Assignees usually file patents in strategic countries for their inventions, such as the most promising markets, economically important regions, the assignee home country or the home country of potential licensors. Still, almost half of ZIKAV patents were filed via simplified patent systems (the Patent Cooperation Treaty system or the European Patent Office), which offer additional time for assignees to decide in which countries to protect their inventions. Given that most of these patents were filed from 2016 onwards, it is still unknown where protection will be sought for this share of patent families.
The markedly collaborative context in which ZIKAV scientific knowledge was generated was evidenced by the co-authorship network analyses. Indeed, several incentives to facilitate multidisciplinary research collaborations were set after the LAC epidemics, such as virtual databases [
36]; the international research consortia ZikAction [
37], ZikAlliance [
38] and ZikaPlan [
39]; the collaborative platforms LabKey Server [
40] and the Global Research Collaboration for Infectious Disease Preparedness (GloPID-R) [
41], among others. The multidisciplinary collaborative work was crucial to characterize the ZIKAV syndrome, in one of the most rapid and coordinated research responses against an emerging disease to date [
42,
43]. In opposition, limited collaboration was evidenced in the patent analyses. However, given the lag time prior to the publication of patent applications, it is possible that the influence of research collaboration will only be observed in the next years.
The patent classification by assignee type evidenced a major role of the academy and academic assignees, as expected from the active response from the scientific community to the 2015–2016 outbreak. Diagnostics was one of the major areas targeted in patent documents, also present in scientific publications.
In Brazil, individuals without affiliation accounted for 60% of the total patent families, whereas the academy was responsible for only 27% of the filings. This may be explained by the focus on vector control, involving the development of low-tech traps and nets, which could possibly be developed without institutional support. According to the WHO, innovative vector control tools that reduce the mosquito population are important technological contributions, amongst the most viable R&D options to help fight the spread of ZIKAV in the immediate future [
44].
This study focused on publications and patents, and it may not include all contributions of LAC countries towards ZIKAV prevention, treatment, and control. However, the S&T indicators described herein are considered valuable tools in policy studies as they objectively assess the diffusion and impact of research, and disclose the geographic origin of the contribution. The use of co-authorship data as an indicator of scientific collaboration has limitations, but, in most cases, it indicates active cooperation in addition to the simple exchange of material or information. We recognize that reviewing only patents with experimental evidence could have resulted in an underestimation of the number of ZIKAV patents filed. We believe that the inclusion of all patent documents regardless of experimental evidence would have produced disputed results.
Conclusions
We reviewed scientific publications, patent records, and co-authorship networks to provide a broad scenario of LAC engagement in research and technological development towards ZIKAV prevention, treatment, and control. The information presented herein has value in informing the global health community and policymakers that (i) LAC countries had a key role in generating and disseminating scientific knowledge on ZIKAV, suggesting a strong research capacity; (ii) LAC countries have expressively contributed to research on ZIKAV clinical manifestations, especially the ones related to effects on newborns; (iii) the Brazilian scientific community was potentially very effective in knowledge sharing and diffusion in the ZIKAV research network, indicating a solid capacity to incentivize and coordinate future LAC collaboration; (iv) Brazil was the single LAC country filing patents, mostly represented by independent inventors and low-tech patents, indicating the need to invest in more technologically advanced areas.
Finally, the high population concentration in major LAC cities and the tropical climate suggest that the region remains vulnerable to ZIKAV and other vector-borne diseases. The need for a continued collaborative and interdisciplinary work, as well as long-term support to strengthen local leadership, is critical to improving LAC capability to prepare for, control and prevent future outbreaks.