Search

Background Deep learning neural networks have shown great promise for the automated analysis of complex medical images. Here we focus on the problem of discriminating malignant from benign lung nodules seen by computed tomography (CT). This is a major public health issue because only about 1 in 20 suspicious lung nodules that are seen on CT, many requiring invasive procedures, are actually cancerous.

Infection caused by the four serotypes of dengue virus (DENV-1-4) is a leading cause of mosquito-borne disease. Clinically-severe dengue disease is more common when secondary dengue infection occurs following prior infection with a heterologous dengue serotype. Other flaviviruses such as yellow fever virus, Japanese encephalitis virus, and Zika virus, can also elicit antibodies which are cross-reactive to DENV. As candidate dengue vaccines become available in endemic settings and for individuals who have received other flavivirus vaccines, it is important to examine vaccine safety and immunogenicity in these flavivirus-experienced populations. We performed a randomized, controlled trial of the National Institutes of Health live attenuated tetravalent dengue vaccine candidate (TV003) in fifty-eight individuals with prior exposure to flavivirus infection or vaccine. As in prior studies of this vaccine in flavivirus-naive volunteers, flavivirus-experienced subjects received two doses of vaccine six months apart and were followed closely for clinical events, laboratory changes, viremia, and neutralizing antibody titers. TV003 was well tolerated with few adverse events other than rash, which was predominately mild. Following one dose, 87% of vaccinees had an antibody response to all four serotypes (tetravalent response), suggesting a robust immune response. In addition, 76% of vaccinees were viremic; mean peak titers ranged from 0.68–1.1 log10 PFU/mL and did not differ by serotype. The second dose of TV003 was not associated with viremia, rash, or a sustained boost in antibody titers indicating that a single dose of the vaccine is likely sufficient to prevent viral replication and thus protect against disease. In comparison to the viremia and neutralizing antibody response elicited by TV003 in flavivirus-naïve subjects from prior studies, we found that subjects who were flavivirus-exposed prior to vaccination exhibited slightly higher DENV-3 viremia, higher neutralizing antibody titers to DENV-2, -3, and -4, and a higher tetravalent response frequency after TV003 administration. In summary, we demonstrate that the NIH tetravalent dengue vaccine TV003 is well-tolerated in flavivirus-experienced individuals and elicits robust post-vaccination neutralizing antibody titers. Trial registration ClinicalTrials.gov NCT01506570, Author summary As live-attenuated dengue vaccine candidates are developed, it is important to ascertain their safety in all populations, regardless of past exposure to dengue, closely related flaviviruses, or similar vaccines. Each of the four dengue virus (DENV) serotypes can cause clinical disease. Severe dengue disease may be life-threatening and is epidemiologically linked to secondary infection with a serotype distinct from the first infection. Candidate tetravalent dengue vaccines are designed to induce neutralizing antibody responses to all serotypes, but confirmation is needed that vaccination itself, as a secondary exposure, is not associated with the development of enhanced reactogenicity. The National Institutes of Health live attenuated tetravalent dengue vaccine candidate, TV003, has previously been shown to be safe and immunogenic in flavivirus-naïve populations. We performed a randomized, placebo-controlled clinical trial of TV003 in individuals previously exposed to flaviviruses and demonstrated tolerability and strong, broad immunogenicity across serotypes. No subjects experienced any dengue-like illness. Vaccine viremia was self-limited and occurred at acceptably low levels compared to those associated with severe dengue from natural infection. TV003 is well-tolerated in healthy adults, regardless of flavivirus exposure, and will be evaluated next in DENV-endemic settings.