The high levels of flaviviruses such as dengue virus and Zika virus in tropical regions highlight their impact on human health and the global economy. A study published in PLOS Neglected Tropical Diseases explored how antibodies produced from prior Zika affect the clinical consequences of dengue. The results indicate that a prior Zika could be a risk factor for severe dengue in subsequent infections. However, we did not observe evidence of antibody-dependent enhancement, such as increased viral load or overexpression of pro-inflammatory cytokines, playing a role in the worsening of subsequent dengue infections.
A screening of 5 epitope libraries comprising a total of 343 non-structural protein 1 (NS1) peptides were tested using detection antibodies previously identified as serotype-specific for NS1 enzyme-linked immunosorbent assay (ELISA) in dengue, along with antibodies specific to Zika. Both peptides demonstrated greater sensitivity than the conventional ELISA using the full NS1 protein. Peptide dengue virus (DENV)-15 achieved a sensitivity of 83% and a specificity of 95%. On the other hand, Peptide DENV-20 exhibited a higher sensitivity of 96%. The peptide related to Zika showed the best overall performance, achieving 97% in both sensitivity and specificity. While capable of identifying seronegative samples, the assays using the full protein were less effective compared to their peptide-based counterparts.
“Our observations suggest that previous Zika infection increased the risk of severe forms of dengue and hospitalizations, similar to what has been observed in secondary dengue infections,” investigators wrote. “In contrast, our study suggests that the observed severity of dengue clinical outcomes don’t seem to be influenced by ADE (increased viral load and anti-inflammatory cytokine levels), as prior infection to dengue was associated with a lower risk for development of severe forms of dengue disease.”
- The study found that antibodies produced from a previous zika infection could increase the risk of severe forms of dengue in subsequent infections.
- By screening epitope libraries of NS1 peptides, the study identified peptide-based assays that demonstrated greater sensitivity and specificity in detecting DENV and ZIKV infections compared to conventional full-protein ELISA tests.
- Notably, the study did not find evidence of ADE worsening dengue outcomes, challenging some existing hypotheses about flavivirus interactions.
The study compared the efficacy of peptide vs. protein-based assays in distinguishing between dengue and Zika infections. This included adding sera that were negative for dengue but positive for Zika in an analysis of the DV-20 peptide against DENV-NS1 assays. Similarly, sera that were negative for zika but positive for dengue were used in ROC analyses for the ZV-54 peptide against Zika virus (ZIKV)-NS1 assays. In these comparative analyses, the peptide-based assays for both viruses showed areas under the curve significantly higher than those achieved by NS1 ELISAs (>0.94 versus 0.66–0.74). The peptides DV-20 (with 96% sensitivity and 98% specificity) and ZV-54 (with 94% sensitivity and 88% specificity) emerged as superior antigenic targets for differentiating between dengue and Zika-specific antibodies.
“Our results demonstrated a significant differentiation potential,” investigators wrote. “To reinforce this, the DV+/ZV+ group was excluded from all analyses to avoid dengue and Zika cross-reactivity in testing. Furthermore, we reasoned that the formation of immune complexes between NS1 and IgG might occur during the acute phase of post-primary infection and interfere with the test’s sensitivity.”
Potential risk factors that could exacerbate the clinical forms of dengue include the correlation between age, specifically children and older adults, and the advancement to more severe forms of the disease. It has been observed that the elderly population, which is more prone to have comorbidities, may need more intensive healthcare interventions, such as hospitalization, when infected. Additionally, the management of these comorbidities renders older adults more susceptible to severe outcomes. However, no statistically significant differences were observed in the distribution of patient ages across the groups (p = 0.121) or in the average age among the groups (p = 0.365).
This study highlights the interactions between different flaviviruses and their hosts, showing that knowledge about dengue serotypes cannot be directly applied to other flaviviruses. It emphasizes the need for diagnostic tools to reduce cross-reactivity between dengue and Zika detection, offering insights into how prior Zika affects subsequent dengue. Although the exact mechanisms leading to severe dengue in individuals previously infected with Zika are not fully understood, this research is important for guiding the development of treatments and improving our understanding of flavivirus interactions.
Estofolete C, Versiani A, Dourado F, Milhim B, Pacca C, et al. Influence of previous zika virus infection on acute dengue episode. PLOS Neglected Tropical Diseases. Published November 9, 2023. Accessed February 8, 2023. https://doi.org/10.1371/journal.pntd.0011710