Ten years of Zika in Brazil: achievements, challenges and perspectives

Abstract

Zika virus (ZIKV) infections have impacted public health in Brazil since 2015, primally due to Congenital Zika Virus Syndrome (CZVS) cases, which may lead to microcephaly and other clinical manifestations, such as hearing and visual impairments. More than ten years after the first diagnosis of Zika in Brazil, some progress has been made and the epidemiological scenario has improved considerably. However, despite these advances, more than a thousand ZIKV infections are reported annually in Brazil and new CZVS cases continue to be observed. Herein, we performed a retrospective and prospective analysis to assess the progress made and identify gaps and challenges that still need to be addressed. Overall, we believe that future ZIKV control efforts in Brazil must include: enhanced vector control measures; surveillance for potential vertebrate reservoirs; medical care for pregnant women, including prevention of infection and vertical transmission; sensitive and specific intrauterine CZVS diagnosis; ongoing support for children and families with CZVS cases; expansion of the national diagnostic network for arboviruses, including encouraging healthcare professionals to perform laboratory tests; assessment of the impactof the dengue vaccine, recently implemented in Brazil, on ZIKV infections; and affordable, sensitive and specific multiplex diagnostic strategies adequately validated for cross-reactivity with other arboviruses circulating in Brazil.

Dear editor

Zika virus infections (ZIKV; now species Orthoflavivirus zikaense) were initially described in Brazil in 2015 from human samples collected earlier that year [1–3]. Subsequently, an increasing number of Zika cases were reported in 2015, resulting in an epidemic that coincided temporally and spatially with an increase in the birth of microcephalic infants. Due to the escalating microcephaly cases, Brazil declared a Public Health Emergency of National Concern on November 11, 2015, which lasted 18 months [4]. On November 28, 2015, the association between ZIKV and microcephaly was reported [5]. Importantly, in addition to microcephaly, other clinical manifestations were observed in these infants, such as hearing and visual disturbances, leading to the term Congenital Zika Virus Syndrome (CZVS) [6, 7]. These findings were unprecedented in the ZIKV’s history and were described first and foremost in Brazil [8]. Herein, we discuss the changing epidemiology of ZIKV in Brazil over the past decade, as well as some advances and gaps in this topic.

Between 2015 and 2025, more than 177,000 Zika cases were confirmed in Brazil, a considerably higher number than observed in other American countries (Figs. 1A and 2) [9, 10]. In Puerto Rico, for example, the second country in the Americas with the highest number of Zika cases in the last decade, fewer than 38,000 Zika cases were recorded (Fig. 2) [10]. Furthermore, the vast majority of Zika cases in Brazil occurred in 2016, particularly in the Southeast and Northeast regions, with the Northeast also being the region most affected by ZIKV-related microcephaly (Fig. 3A and B).

Fig. 1.

Numbers of Zika, microcephaly and dengue cases in the last decade in Brazil. Zika, microcephaly and dengue cases were collected from the Ministry of Health (DataSUS) [9, 12, 35]. (A) Zika and microcephaly cases are available from 2015 to 2025 and 2015 to 2023, respectively; (B) Both Zika and dengue cases are available for 2015 to 2025; 486 Zika cases in 2015. Forty-nine Zika cases, with unknown epidemiological year, were not plotted

Fig. 2.

Number of Zika cases in the Americas between 2015 and 2025. The ten countries with the highest numbers of Zika cases are listed: Brazil (178,517), Puerto Rico (37,488), Mexico (12,934), Colombia (10,337), Costa Rica (9,947), Panama (6,130), Peru (3,613), Ecuador (3,008), Curaçao (2,020) and Bolivia (1,382). Data available from the Pan American Health Organization (PAHO) [10]

Fig. 3.

Number of Zika (A) and microcephaly (B) cases by region in Brazil (2015–2025). CW: Central-West; N: North; NE: Northeast; S: South; SE: Southeast. Data collected from the Ministry of Health (DataSUS) [9, 35]

The sharp decline in Zika cases in the years immediately following 2016 is consistent with improved public health measures to control Aedes vectors (Fig. 1A). In 2016, the Brazilian government launched a massive national campaign against the Aedes mosquito, which included educational initiatives, training for healthcare professionals and efforts by the population and the armed forces to eliminate breeding sites [11]. This strategy may have contributed to the reduction in Zika cases in the years immediately following 2016; however, it alone is not sufficient to explain the persistent low incidence of Zika in subsequent years. This is particularly evident in 2024, when Brazil experienced the largest recorded dengue epidemic, with almost 6 million confirmed cases [12], while Zika diagnoses remained low, totaling only 1,981 cases (Fig. 1B), of which 1,561 were confirmed by laboratory tests and 389 by clinical-epidemiological criteria; the diagnostic approach was not recorded in 31 confirmed cases [9]. Given that dengue virus (DENV) and ZIKV share the same arthropod vector, it is reasonable to conclude that vector control would not be sufficient to explain the decline in Zika cases in recent years.

The reduction in Zika cases is likely multifactorial, with several factors contributing to the current epidemiological scenario. For example, it has been described that co-infection of Brazilian Aedes mosquitoes with chikungunya (CHIKV) and ZIKV or DENV and ZIKV may decrease vector competence for ZIKV by 10%. Although this reduction may seem modest, in a multifactorial context where multiple factors interact, it could still play an important role in the epidemiology of Zika [13].

Furthermore, herd immunity induced by natural exposure to ZIKV over the years could partially explain the sustained decline of Zika in Brazil. This hypothesis is further supported by the fact that ZIKV has only one described serotype, therefore, infection with one viral variant would likely confer protective immunity against others [14, 15]. In addition, it is important to emphasize that most Zika cases are asymptomatic [16], which reduces testing demand and affects the number of reported cases.

Despite the plausibility of the herd immunity hypothesis, it is important to consider the complexity of ZIKV immunity and investigate key issues in greater depth, including the duration of immunity after ZIKV infection and the influence of DENV antibodies on ZIKV infection. Some studies conducted on humans [17] and animal models (rhesus macaques) [18] have suggested that humoral immunity after ZIKV infection could last approximately two years, while other authors have suggested ZIKV reinfection within six months [19]. In this context, it is reasonable to assume that immunity after ZIKV infection is also multifactorial, depending on several factors, including the immunogenicity of the first infection, considering the viral load and the host's immune status, and the viral load in the second infection. Furthermore, it is important to consider that, although sterilizing immunity may be short-lived, the remaining effective immunity could contribute to a better response to a second infection, similar to an effective immunity, resulting in milder symptoms and reduced need for diagnosis. Continuous exposure to ZIKV in an endemic area could also act as an immunity booster, providing longer-lasting protection than that provided by a single initial infection.

The dynamics of ZIKV cases in Brazil must also account for its co-circulation with DENV. Herein, DENV antibodies could cross-react with ZIKV, neutralizing or enhancing the infection through the antibody-dependent enhancement (ADE) mechanism [20, 21]. This dual role of DENV antibodies in ZIKV infection likely depends on host- and viral-related factors, such as antibody titer, monotypic or multitypic immune status [22] and DENV serotype [23]. Interestingly, beyond potential ADE or cross-neutralization, prior exposure to DENV could be modulate immunity to ZIKV, influencing it positively [24, 25] or negatively [26]. Although these issues have been extensively investigated, it remains important to further explore them in Brazil, where DENV is endemic and a national dengue vaccination campaign has recently been launched [27]. The potential impact of this campaign on ZIKV infection should be carefully monitored.

In addition to the likely reasons for the decrease in reported Zika cases, it is important to identify potential factors contributing to the persistence of ZIKV in Brazil, including possible vector-to-vector transmission (horizontal and/or vertical) and a sylvatic cycle, for example, involving non-human primates (NHPs) [28–32]. Although the relevance of vector-to-vector transmission and the sylvatic cycle for ZIKV epidemiology remains uncertain, with few recent findings corroborating their role in viral circulation, a study conducted with mosquitoes collected between 2018 and 2019, when Zika cases had already declined, detected ZIKV RNA in pools of Ae. albopictus and Haemagogus leucocelaenus collected in areas with low human interference in Rio de Janeiro, Brazil. Viral RNA was also detected in adult mosquitoes reared from eggs collected in the field [33]. Overall, these findings suggest the potential circulation of ZIKV in sylvatic settings, as well as its probable natural vertical transmission, highlighting the need for ZIKV surveillance beyond urban areas [33]. The importance of this issue has also been discussed by other authors, even in the face of a lack of evidence of ZIKV circulation in NHPs in some Brazilian states [34].

In line with the decline in Zika cases, the number of ZIKV-related microcephaly cases also decreased markedly in Brazil between 2015 and 2023 (Fig. 1A and Fig. 3B). While these recent data provide some reassurance, infants with microcephaly caused by ZIKV infection are still being born in Brazil, an epidemiological scenario that cannot be overlooked. Considering the last three years with available data (2021–2023), the number of ZIKV-related microcephaly cases in Brazil ranged from four to eight cases per year (Fig. 1A and Fig. 3B) [35].

The continued birth of microcephalic infants nearly 10 years after the first Zika case reported in Brazil highlights the ongoing need for public health measures to mitigate the consequences of ZIKV infection, including socioeconomic impacts, such as: prenatal care and long-term assistance for pregnant women and children with CZVS, continued and effective vector control, and the development of antivirals and vaccines for pregnant women to prevent vertical viral transmission. Importantly, some of these issues have already been considerably addressed in Brazil. The country has invested in and scaled up the production and release de Wolbachia-infected Ae. aegypti, which drastically reduces the vector competence for ZIKV, DENV and CHIKV transmission [36–38]. Furthermore, due to the persistent impact of CZVS cases, the Brazilian government instituted financial compensation for the families with CZVS [39] and a lifetime pension for affected children [40].

It is also worth noting that the Brazilian public health service provides medical follow-up for pregnant women suspected of Zika infection [41]. However, considering that most ZIKV infections are asymptomatic [16] and that even asymptomatic pregnant women may transmit ZIKV vertically [42], early identification of potential CZVS cases remains challenging. This is an important issue, as routine examinations may fail to detect CZVS cases, which are not always associated with microcephaly at birth. Moreover, this issue also raises the need for long-term follow-up to identify delayed neurological damage [43, 44]. Regarding measures to prevent infection in pregnant women and vertical ZIKV transmission, several vaccines are under evaluation, including phase 1 and 2 clinical trials, but none have been licensed to date [45]. There are also no licensed antiviral drugs for ZIKV [46]; herein, candidate drugs must be able to prevent vertical transmission without posing teratogenic risks.

Diagnostic strategies for Zika have improved considerably since 2015. Numerous commercial and in house molecular approaches have been developed for ZIKV detection, including RT-PCR, RT-qPCR, RT-ddPCR, RT-RPA, RT-LAMP, and CRISPR-based platforms [47–49]. Multiplex approaches have also been established for the simultaneous and differential detection of ZIKV and other arboviruses, such as DENV and CHIKV [50, 51]. Multiplex kits for molecular detection of DENV, ZIKV and CHIKV have been produced in Brazil and distributed to its 27 Central Public Health Laboratories (in Portuguese: Laboratórios Centrais de Saúde Pública, LACEN), thereby improving the diagnosis of Zika cases in recent years. Indeed, an increase in laboratory-confirmed Zika cases has been observed in all regions of Brazil (Fig. 4). Table 1 lists some molecular assays developed and/or used in Brazil for the laboratory investigation of suspected Zika cases.

Fig. 4.

Laboratory-confirmed Zika cases by region in Brazil (2015–2025). CW: Central-West; N: North; NE: Northeast; S: South; SE: Southeast. Data collected from the Ministry of Health (DataSUS) [9]

Table 1.

Molecular assays developed and/or used in Brazil for the laboratory diagnosis of Zika cases

Strategy	Availability	Targets	Sensitivity (95% CI1)	Specificity2 (95% CI)	LoD3	References
RT-LAMP	In house	ZIKV	100% (83.16–100.00%)	93.75% (86.01–97.94%)	−1.07 log10 PFU4	[66]
RT-PCR	In house	ZIKV	NA5	NA6	7.7 PFU/reaction	[67]
RT-qPCR (probe)	In house	ZIKV	NA5	NA6	25 or 100 copies/mL7	[68]
RT-qPCR (probe)	ZDC molecular assay (Bio-Manguinhos, Brazil)	ZIKV, DENV and CHIKV (multiplex)	ZIKV: 100% (71.5–100%) DENV: 100% (59–100%) CHIKV: 100% (86.8–100%)	ZIKV: 100% (97.2–100%) DENV: 100% (97.3–100%) CHIKV: 100% (96.2–100%)	ZIKV: 12.9 PFU/mL; 105.3 copies/mL DENV: 4.1–221.5 PFU/mL8; 1.60 copies/mL CHIKV: 50 PFU/mL; 195.8 copies/mL	[69]
			NA5	99.6–100%	ZIKV: 8.99 copies/mL DENV: 100 copies/mL CHIKV: 480 copies/mL	[70]
RT-qPCR (probe)	Biomol ZDC (IBMP, Brazil)	ZIKV, DENV and CHIKV (multiplex)	CHIKV: 100% ZIKV: 100% DENV: 94.7–100%9	100%	ZIKV: 5 PFU/mL CHIKV: 5 PFU/mL DENV: 95–684 copies/reaction10	[71]
RT-qPCR (probe)	Bio Gene Zika Virus PCR Kit (Bioclin-Quibasa, Brazil)	ZIKV	99.9%	99.9%	28 copies/mL	[72]
RT-qPCR (probe)	TaqMan® Arbovirus Kit (Applied Biosystems™,US)	ZIKV, DENV and CHIKV (multiplex)	ZIKV: 100% DENV: 97.98% CHIKV: 100%	ZIKV: 100% DENV: 99.26% CHIKV: 100%	NA5	[73]

¹Confidence interval

²Data on the analytical specificity of some assays are available in the references

³Limit of detection

⁴Plaque-forming unit

⁵Not available

⁶Not available (data available for analytical specificity only)

⁷Sensitivity depends on the primers and probes set

⁸DENV1: 221.5 PFU/mL; DENV2: 4.1 PFU/mL; DENV3: 23.8 PFU/mL; DENV4: 9.2 PFU/mL

⁹DENV1: 94.7%; DENV2-4: 100%

¹⁰DENV1: 129 copies/reaction DENV2: 494 copies/reaction; DENV3: 95 copies/reaction; DENV4: 684 copies/reaction

In addition to laboratory confirmation of Zika cases, it is important that suspected cases of other arboviruses, particularly DENV and CHIKV, also undergo laboratory testing. For example, in 2024, almost four million dengue cases were confirmed in Brazil based on clinical-epidemiological criteria [52], which does not exclude possible misdiagnoses, as well as co-infections by ZIKV and CHIKV. Furthermore, it is essential to raise awareness among healthcare professionals about the importance of laboratory investigation of suspected arboviral cases and to improve laboratories' access to clinical samples, including by expanding and decentralizing the network of Central Public Health Laboratories across Brazil.

Several serological tests for detecting antigens or antibodies against ZIKV have also been developed since 2015, including immunochromatographic tests (rapid tests) and ELISA [53]. A major pitfall of serological methods is their limited specificity, particularly regarding cross-reactivity between ZIKV and other orthoflaviviruses, especially DENV [54]. This issue is particularly relevant in Brazil, a DENV-endemic country, where millions of cases have been reported in recent years [12]. Furthermore, other orthoflaviviruses, such as West Nile (WNV), Ilheus (ILHV), Rocio (ROCV) and Saint Louis encephalitis (SLEV) viruses, also circulate in Brazil and may complicate the serological diagnosis of Zika [23, 55, 56]. Several ELISA tests have been used in Brazil for the diagnosis or serological surveillance of Zika, including Zika virus (IgM) (Euroimmun) [57], Zika virus (IgG) (Euroimmun) [57] Dia.Pro IgM [58], Dia.Pro IgG [58] and Zika virus IgG capture Elisa kit (Novatec) [59], with diagnostic performance (sensitivity and specificity) varying considerably depending on the stage of infection, population and region analyzed [57].

The plaque reduction neutralization test (PRNT) is the gold standard and the most specific serological test [60, 61]. Indeed, PRNT offers several advantages over conventional serological methods, however, its implementation faces multiple challenges, including intensive and time-consuming procedures, the need for trained professionals, high cost, and appropriate laboratory infrastructure. Overall, the ideal diagnostic approach for Zika in Brazil should combine simplicity and low cost, multiplex strategies and point-of-care applicability, which could be achieved through the development and implementation of properly validated multiplex rapid tests.

Given the lack of laboratory testing that persists in Brazil, some Zika diagnoses continue to be based on clinical-epidemiological criteria. The challenge here is even greater, as, in addition to differentiating ZIKV from other orthoflaviviruses, it is also necessary to distinguish Zika cases from those caused by other arboviruses, such as Alphavirus (e.g., CHIKV and Mayaro virus, MAYV). To improve this process, the Brazilian Ministry of Health has published a guide for the differential diagnosis of dengue, Zika and chikungunya, which includes the assessment of both clinical and laboratory parameters, such as lymphopenia and thrombocytopenia [6, 62, 63]. Moreover, in 2024, Brazil experienced the largest recorded spread of Oropouche virus (OROV) [52, 64], making it an additional target for the differential diagnosis of Zika [65].

In summary, after nearly ten years of ZIKV circulation in Brazil, it is crucial to analyze the country's progress and persistent challenges. This retrospective and prospective reflection is important both for understanding the advances achieved and for identifying gaps that still need to be addressed by the scientific community and public health authorities. Finally, the next steps to combat ZIKV in Brazil should include the following measures: i) enhanced vector control, including continuous large-scale educational campaigns; ii) surveillance of potential vertebrate reservoirs; iii) prenatal care, including prevention of infection and vertical transmission through vaccination and antivirals (when available); iv) sensitive and specific intrauterine CZVS diagnosis; v) ongoing support for children and families affected by CZVS; vi) expansion of the national diagnostic network for arboviruses, including initiatives to encourage healthcare professionals to perform laboratory testing; vii) assessment of the impact of the dengue vaccine, recently implemented in Brazil, on ZIKV infections; and viii) affordable multiplex diagnostic strategies that combine high sensitivity and specificity, properly validated for cross-reactivity with other arboviruses circulating in Brazil.

Author contributions

FYS: Conceptualization, Methodology, Investigation, Visualization, Writing – original draft; GCNT: Conceptualization, Methodology, Investigation, Visualization; EFF: Conceptualization, Visualization, Writing-review; TRRL: Investigation, Visualization, Writing-review; RFC: Investigation, Visualization, Writing-review; EFF: Visualization, Writing-review; JVJSJr: Conceptualization, Methodology, Visualization, Writing-review & editing, Supervision.

Funding

This study received no funding.

Data availability

The data supporting the study results are in the public domain and can be accessed in the cited references and websites.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.