Ethics of a partially effective dengue vaccine: Lessons from the Philippines

Dengvaxia, a chimeric yellow fever tetravalent dengue vaccine developed by SanofiPasteur is widely licensed in dengue-endemic countries. In a large cohort study Dengvaxia was found to partially protect children who had prior dengue virus (DENV) infections but sensitized seronegative children to breakthrough DENV disease of enhanced severity. In 2019, the European Medicines Agency and the US FDA issued licenses that reconciled safety issues by restricting vaccine to individuals with prior dengue infections. Using revised Dengvaxia efficacy and safety data we sought to estimate hospitalized and severe dengue cases among the more than 800,000 9 year-old children vaccinated in the Philippines. Despite an overall vaccine efficacy of 69% during 4 years post-vaccination we project there will be more than one thousand vaccinated seronegative and seropositive children hospitalized for severe dengue. Assisting these children through a program of enhanced surveillance leading to improved care deserves widespread support. Clinical responses observed during breakthrough dengue infections in vaccinated individuals counsel prudence in design of vaccine policies. Recommendations concerning continued use of this dengue vaccine are: (1) obtain a better definition of vaccine efficacy and safety through enhanced phase 4 surveillance, (2) obtain a valid, accessible, sensitive, specific and affordable serological test that identifies past wild-type dengue virus infection and (3) clarify safety and efficacy of Dengvaxia in flavivirus immunes. In the absence of an acceptable serological screening test these unresolved ethical issues suggest Dengvaxia be given only to those signing informed consent.Marie Skłodowska-Curie grant agreement No 79249

Effects of infection history on dengue virus infection and pathogenicity

The understanding of immunological interactions among the four dengue virus (DENV) serotypes and their epidemiological implications is often hampered by the lack of individuallevel infection history. Using a statistical framework that infers full infection history, we analyze a prospective pediatric cohort in Nicaragua to characterize how infection history modulates the risks of DENV infection and subsequent clinical disease. After controlling for age, one prior infection is associated with 54% lower, while two or more are associated with 91% higher, risk of a new infection, compared to DENV-naive children. Children >8 years old have 55% and 120% higher risks of infection and subsequent disease, respectively, than their younger peers. Among children with ≥1 prior infection, intermediate antibody titers increase, whereas high titers lower, the risk of subsequent infection, compared with undetectable titers. Such complex dependency needs to be considered in the design of dengue vaccines and vaccination strategies

Reconstruction of antibody dynamics and infection histories to evaluate dengue risk.

As with many pathogens, most dengue infections are subclinical and therefore unobserved 1 . Coupled with limited understanding of the dynamic behaviour of potential serological markers of infection, this observational problem has wide-ranging implications, including hampering our understanding of individual- and population-level correlates of infection and disease risk and how these change over time, between assay interpretations and with cohort design. Here we develop a framework that simultaneously characterizes antibody dynamics and identifies subclinical infections via Bayesian augmentation from detailed cohort data (3,451 individuals with blood draws every 91 days, 143,548 haemagglutination inhibition assay titre measurements)2,3. We identify 1,149 infections (95% confidence interval, 1,135-1,163) that were not detected by active surveillance and estimate that 65% of infections are subclinical. After infection, individuals develop a stable set point antibody load after one year that places them within or outside a risk window. Individuals with pre-existing titres of ≤1:40 develop haemorrhagic fever 7.4 (95% confidence interval, 2.5-8.2) times more often than naive individuals compared to 0.0 times for individuals with titres >1:40 (95% confidence interval: 0.0-1.3). Plaque reduction neutralization test titres ≤1:100 were similarly associated with severe disease. Across the population, variability in the size of epidemics results in large-scale temporal changes in infection and disease risk that correlate poorly with age

Impacts of Zika emergence in Latin America on endemic dengue transmission

In 2015 and 2016, Zika virus (ZIKV) swept through dengue virus (DENV) endemic areas of Latin America. These viruses are of the same family, share a vector and may interact competitively or synergistically through human immune responses. We examine dengue incidence from Brazil and Colombia before, during, and after the Zika epidemic. We find evidence that dengue incidence was atypically low in 2017 in both countries. We investigate whether subnational Zika incidence is associated with changes in dengue incidence and find mixed results. Using simulations with multiple assumptions of interactions between DENV and ZIKV, we find cross-protection suppresses incidence of dengue following Zika outbreaks and low periods of dengue incidence are followed by resurgence. Our simulations suggest correlations in DENV and ZIKV reproduction numbers could complicate associations between ZIKV incidence and post-ZIKV DENV incidence and that periods of low dengue incidence are followed by large increases in dengue incidence

A tetravalent live attenuated dengue virus vaccine stimulates balanced immunity to multiple serotypes in humans

The four-dengue virus (DENV) serotypes infect several hundred million people annually. For the greatest safety and efficacy, tetravalent DENV vaccines are designed to stimulate balanced protective immunity to all four serotypes. However, this has been difficult to achieve. Clinical trials with a leading vaccine demonstrated that unbalanced replication and immunodominance of one vaccine component over others can lead to low efficacy and vaccine enhanced severe disease. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a live attenuated tetravalent DENV vaccine (TV003), which is currently being tested in phase 3 clinical trials. Here we report, our study to determine if TV003 stimulate balanced and serotype-specific (TS) neutralizing antibody (nAb) responses to each serotype. Serum samples from twenty-one dengue-naive individuals participated under study protocol CIR287 (ClinicalTrials.gov NCT02021968) are analyzed 6 months after vaccination. Most subjects (76%) develop TS nAbs to 3 or 4 DENV serotypes, indicating immunity is induced by each vaccine component. Vaccine-induced TS nAbs map to epitopes known to be targets of nAbs in people infected with wild type DENVs. Following challenge with a partially attenuated strain of DENV2, all 21 subjects are protected from the efficacy endpoints. However, some vaccinated individuals develop post challenge nAb boost, while others mount post-challenge antibody responses that are consistent with sterilizing immunity. TV003 vaccine induced DENV2 TS nAbs are associated with sterilizing immunity. Our results indicate that nAbs to TS epitopes on each serotype may be a better correlate than total levels of nAbs currently used for guiding DENV vaccine development

Antibody landscapes after influenza virus infection or vaccination.

We introduce the antibody landscape, a method for the quantitative analysis of antibody-mediated immunity to antigenically variable pathogens, achieved by accounting for antigenic variation among pathogen strains. We generated antibody landscapes to study immune profiles covering 43 years of influenza A/H3N2 virus evolution for 69 individuals monitored for infection over 6 years and for 225 individuals pre- and postvaccination. Upon infection and vaccination, titers increased broadly, including previously encountered viruses far beyond the extent of cross-reactivity observed after a primary infection. We explored implications for vaccination and found that the use of an antigenically advanced virus had the dual benefit of inducing antibodies against both advanced and previous antigenic clusters. These results indicate that preemptive vaccine updates may improve influenza vaccine efficacy in previously exposed individuals.This is the author’s version of the work. It will be under embargo for 6 months following publication. It is posted here by permission of the AAAS for personal use, not for redistribution. The final version is available from AAAS in Science at http://www.sciencemag.org/content/346/6212/996.long

Dengue viruses cluster antigenically but not as discrete serotypes.

The four genetically divergent dengue virus (DENV) types are traditionally classified as serotypes. Antigenic and genetic differences among the DENV types influence disease outcome, vaccine-induced protection, epidemic magnitude, and viral evolution. We characterized antigenic diversity in the DENV types by antigenic maps constructed from neutralizing antibody titers obtained from African green monkeys and after human vaccination and natural infections. Genetically, geographically, and temporally, diverse DENV isolates clustered loosely by type, but we found that many are as similar antigenically to a virus of a different type as to some viruses of the same type. Primary infection antisera did not neutralize all viruses of the same DENV type any better than other types did up to 2 years after infection and did not show improved neutralization to homologous type isolates. That the canonical DENV types are not antigenically homogeneous has implications for vaccination and research on the dynamics of immunity, disease, and the evolution of DENV.This research was supported in part by the Intramural Research Program of the US NIH, National Institute of Allergy and Infectious Diseases, European Union (EU) FP7 programs EMPERIE (223498) and ANTIGONE (278976), Human Frontier Science Program (HFSP) program grant P0050/2008, the NIH Director’s Pioneer Award DP1-OD000490-01, the FIRST program from the Bill and Melinda Gates Foundation and the Instituto Carlos Slim de la Salud (E.H.). The antigenic cartography toolkit was in part supported by NIAID-NIH Centers of Excellence for Influenza Research and Surveillance contracts HHSN266200700010C and HHSN272201400008C for use on influenza virus. L.C.K. was supported by the Gates Cambridge Scholarship and the NIH Oxford Cambridge Scholars Program. J.M.F. was supported by an MRC Fellowship (MR/K021885/1) and a Junior Research Fellowship from Homerton College Cambridge. E.C.H. was supported by an NHMRC Australia Fellowship. N.V. and R.B.T were supported by NIH contract HHSN272201000040I/HHSN27200004/D04.This is the author accepted manuscript. The final version is available from AAAS via http://dx.doi.org/10.1126/science.aac501

Reconstruction of antibody dynamics and infection histories to evaluate dengue risk

As with many pathogens, most dengue infections are subclinical and therefore unobserved 1 . Coupled with limited understanding of the dynamic behaviour of potential serological markers of infection, this observational problem has wide-ranging implications, including hampering our understanding of individual- and population-level correlates of infection and disease risk and how these change over time, between assay interpretations and with cohort design. Here we develop a framework that simultaneously characterizes antibody dynamics and identifies subclinical infections via Bayesian augmentation from detailed cohort data (3,451 individuals with blood draws every 91 days, 143,548 haemagglutination inhibition assay titre measurements) 2,3 . We identify 1,149 infections (95% confidence interval, 1,135-1,163) that were not detected by active surveillance and estimate that 65% of infections are subclinical. After infection, individuals develop a stable set point antibody load after one year that places them within or outside a risk window. Individuals with pre-existing titres of ≤1:40 develop haemorrhagic fever 7.4 (95% confidence interval, 2.5-8.2) times more often than naive individuals compared to 0.0 times for individuals with titres >1:40 (95% confidence interval: 0.0-1.3). Plaque reduction neutralization test titres ≤1:100 were similarly associated with severe disease. Across the population, variability in the size of epidemics results in large-scale temporal changes in infection and disease risk that correlate poorly with age

Access to Adequate Outpatient Depression Care for Mothers in the USA: A Nationally Representative Population-Based Study

Maternal depression is often untreated, resulting in serious consequences for mothers and their children. Factors associated with receipt of adequate treatment for depression were examined in a population-based sample of 2,130 mothers in the USA with depression using data from the 1996–2005 Medical Expenditure Panel Survey. Chi-squared analyses were used to evaluate differences in sociodemographic and health characteristics by maternal depression treatment status (none, some, and adequate). Multivariate regression was used to model the odds of receiving some or adequate treatment, compared to none. Results indicated that only 34.8% of mothers in the USA with depression received adequate treatment. Mothers not in the paid workforce and those with health insurance were more likely to receive treatment, while minority mothers and those with less education were less likely to receive treatment. Understanding disparities in receipt of adequate treatment is critical to designing effective interventions, reducing treatment inequities, and ultimately improving the mental health and health of mothers and their families