Dengue Virus Neutralizing Antibody Levels Associated with Protection from Infection in Thai Cluster Studies

Abstract

BackgroundLong-term homologous and temporary heterologous protection from dengue virus (DENV) infection may be mediated by neutralizing antibodies. However, neutralizing antibody titers (NTs) have not been clearly associated with protection from infection.Methodology/Principal FindingsData from two geographic cluster studies conducted in Kamphaeng Phet, Thailand were used for this analysis. In the first study (2004–2007), cluster investigations of 100-meter radius were triggered by DENV-infected index cases from a concurrent prospective cohort. Subjects between 6 months and 15 years old were evaluated for DENV infection at days 0 and 15 by DENV PCR and IgM ELISA. In the second study (2009–2012), clusters of 200-meter radius were triggered by DENV-infected index cases admitted to the provincial hospital. Subjects of any age ≥6 months were evaluated for DENV infection at days 0 and 14. In both studies, subjects who were DENV PCR positive at day 14/15 were considered to have been “susceptible” on day 0. Comparison subjects from houses in which someone had documented DENV infection, but the subject remained DENV negative at days 0 and 14/15, were considered “non-susceptible.” Day 0 samples were presumed to be from just before virus exposure, and underwent plaque reduction neutralization testing (PRNT). Seventeen “susceptible” (six DENV-1, five DENV-2, and six DENV-4), and 32 “non-susceptible” (13 exposed to DENV-1, 10 DENV-2, and 9 DENV-4) subjects were evaluated. Comparing subjects exposed to the same serotype, receiver operating characteristic (ROC) curves identified homotypic PRNT titers of 11, 323 and 16 for DENV-1, -2 and -4, respectively, to differentiate “susceptible” from “non-susceptible” subjects.Conclusions/SignificancePRNT titers were associated with protection from infection by DENV-1, -2 and -4. Protective NTs appeared to be serotype-dependent and may be higher for DENV-2 than other serotypes. These findings are relevant for both dengue epidemiology studies and vaccine development efforts.

Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort

“…A recent index-cluster study in Thailand found that individuals with symptomatic infections had lower preinfection NAb titers than a comparable group of individuals likely, but not definitely, exposed to DENV but who did not become ill (18). However, because of study limitations, these findings collectively do not provide definitive proof of the relationship between NAb titers and protection: The protective effect was not consistently observed against all DENV serotypes (17); the DENV-negative individuals may not have been exposed to DENV (18); and the magnitude of NAb titers was not directly analyzed (12,19). Beyond dengue cohort studies, there remains concern that NAb titers measured with nonhuman cell substrates are not as biologically relevant (13).…”

“…Previous longitudinal cohort studies in Thailand found that preinfection NAb titers reduce the risk of severe disease (17), whereas studies in Sri Lanka and Peru found that the number of DENV serotypes that were detectably neutralized reduced the risk of symptomatic compared with inapparent 2°DENV infection (12,19). A recent index-cluster study in Thailand found that individuals with symptomatic infections had lower preinfection NAb titers than a comparable group of individuals likely, but not definitely, exposed to DENV but who did not become ill (18). However, because of study limitations, these findings collectively do not provide definitive proof of the relationship between NAb titers and protection: The protective effect was not consistently observed against all DENV serotypes (17); the DENV-negative individuals may not have been exposed to DENV (18); and the magnitude of NAb titers was not directly analyzed (12,19).…”

“…In studies of infants, who receive IgG antibodies by transplacental transfer from DENV-immune mothers, infants with higher NAb titers at birth generally, although not always, experienced symptomatic disease later than those with lower titers (14)(15)(16). Recent studies in children and adults have made important advances in demonstrating an association between the quantity of cross-reactive preinfection NAb titers and reduced risk of symptomatic secondary (2°) infection, defined as two or more infections, but have not been conclusive: the association did not hold for all DENV serotypes (15,17); exposure could not be proven for DENV-negative individuals (18); or the magnitude of preinfection NAb titers was not directly studied (12,19). Thus, there is an urgent need to definitively establish whether NAb titers correlate with protection in endemic settings.…”

Dengue vaccine–induced CD8+ T cell immunity confers protection in the context of enhancing, interfering maternal antibodies

“…Strong evidence supports a role for neutralizing antibodies and the 50% neutralizing (PRNT 50 ) titer is widely adopted as a surrogate marker for vaccine efficacy (11)(12)(13). Although the presence of neutralizing antibodies may be associated with a lower risk of disease, a clear correlation between a defined level of neutralization and protection from any serotype remains to be established (14,15). In particular, CYD-TDV (Dengvaxia), the first human-approved DENV vaccine, elicited generally high neutralizing titers in vaccinees but the overall protective efficacy across all 4 DENV serotypes was only 60.3% (16).…”

Monitoring and improving the sensitivity of dengue nested RT-PCR used in longitudinal surveillance in Thailand

“…It continues to be widely used in clinical, epidemiological and entomological studies [6][7][8][24][25][26][27][28][29]. Nonetheless, due to the accumulated spatiotemporally-dependent changes in the virus genome, continuous monitoring of assay sensitivity is required to ensure the validity and accuracy of the assay.…”