Serological Evidence of Widespread Zika Transmission across the Philippines

Abstract

Zika virus (ZIKV) exposure across flavivirus-endemic countries, including the Philippines, remains largely unknown despite sporadic case reporting and environmental suitability for transmission. Using laboratory surveillance data from 2016, 997 serum samples were randomly selected from suspected dengue (DENV) case reports across the Philippines and assayed for serological markers of short-term (IgM) and long-term (IgG) ZIKV exposure. Using mixture models, we re-evaluated ZIKV IgM/G seroprevalence thresholds and used catalytic models to quantify the force of infection (attack rate, AR) from age-accumulated ZIKV exposure. While we observed extensive ZIKV/DENV IgG cross-reactivity, not all individuals with active DENV presented with elevated ZIKV IgG, and a proportion of dengue-negative cases (DENV IgG-) were ZIKV IgG-positive (14.3%, 9/63). We identified evidence of long-term, yet not short-term, ZIKV exposure across Philippine regions (ZIKV IgG+: 31.5%, 314/997) which was geographically uncorrelated with DENV exposure. In contrast to the DENV AR (12.7% (95%CI: 9.1–17.4%)), the ZIKV AR was lower (5.7% (95%CI: 3–11%)) across the country. Our results provide evidence of widespread ZIKV exposure across the Philippines and suggest the need for studies to identify ZIKV infection risk factors over time to better prepare for potential future outbreaks.

Detection of anti-premembrane antibody as a specific marker of four flavivirus serocomplexes and its application to serosurveillance in endemic regions

“…The ZIKV outbreak in the Americas has drawn renewed interest in the epidemiology and transmission of ZIKV in other parts of the world (15). Several lines of evidence including documented Zika cases among travelers from Southeast Asia, retrospective analysis of archived samples, and enhanced surveillance suggested that ZIKV has been circulating at a low but sustained level in several countries in Southeast Asia including the Philippines [46][47][48][49][50][51][52]. Consistent with these reports, we found approximately 10% of the participants from the Philippines had previous ZIKV or ZIKV and DENV infections [51,52].…”

Combining rapid diagnostic tests to estimate primary and post-primary dengue immune status at the point of care

“…In contrast, some with elevated ELISA antibody response were negative for corresponding antibody RDTs. This trend could be attributed to ELISAs, yet not RDTs, cross-reacting with other flaviviruses including ZIKV which has shown to be potentially widespread across dengue-endemic countries [ 30 – 32 ]. It is now well established commercial DENV ELISAs cross-react with ZIKV [ 40 , 41 ] yet whether DENV antibody rapid tests cross-react with ZIKV remains poorly characterised and deserves further attention [ 25 , 42 ].…”

“…Among active cases on disease day 3 to 5, individuals with IgG:IgM ratios above and below 0.45 were categorised as post-primary and primary respectively. As a consequence of previous findings [ 12 , 32 ], post-primary cases included current DENV infections with at least one previous flavivirus infection including DENV and or ZIKV. An overview of the reference DENV immune status classification is shown in S1 File .…”

“…This suggested some patients had historical ZIKV exposure that primed individuals for a subsequent post-primary-like, instead of a primary-like, DENV infection upon their first infection with DENV. Moreover, further analysis suggested post-primary DENV infections with prior ZIKV exposure were at risk of adverse clinical symptoms [ 32 ] which has been previously reported in Nicaragua [ 33 ]. These findings suggested that individuals categorised as post-primary DENV infections include those with either prior exposure to DENV and/or other flaviviruses [ 12 ].…”

“…The novel algorithm achieved 90% agreement with the WHO gold standard method for categorising immune status based on paired sera and proved superior to the Panbio method for classifying immune status [ 11 , 12 ]. Given dengue serological assays have been shown to detect cross-reactive antibodies elicited from other flavivirus infections, including Zika virus (ZIKV) which is often co-endemic with dengue [ 30 – 32 ], previous analysis explored the impact of ZIKV exposure on the generated DENV immune status algorithm [ 12 ]. Results revealed a proportion of those with post-primary, opposed to primary, DENV infections had evidence of ZIKV IgG but not IgM exposure.…”