Rapid travel to a Zika vaccine: are we heading towards success or more questions?

Introduction: The emergence of the Zika virus (ZIKV) in Latin America in 2015-2016 led to an expeditious search for vaccine candidates, with a DNA-based candidate having progressed to Phase II. However, several features of ZIKV infection and epidemiology are not understood, which may be key to maximizing efficacy and ensuring safety of ZIKV vaccines. Areas covered: Conceivable problems related to vaccine development and policy include: (1) paucity of diagnostics to satisfactorily discriminate between past ZIKV and dengue virus (DENV) exposure; (2) insufficient knowledge of the mechanisms of ZIKV neurovirulence, amongst other unknowns in the biology of this infection, is particularly relevant from a vaccine safety perspective; and (3) the potential for disease enhancement, as observed with DENV infection and vaccine. Expert opinion: Vaccine candidates that entered phase I/II trials have demonstrated protection in naïve animal models, while ZIKV epidemics occurred in populations that had encountered DENV before. The resulting cross-reactive antibodies pose problems for reliable serologic diagnostic assays, and for the potential of disease enhancement. The alleged neurological complications also warrant further exploration in order to reassure regulators of the safety profile of these vaccines in target populations. These research aspects should be an integral part of the efforts to develop a vaccine.</p

Rapid travel to a Zika vaccine: are we heading towards success or more questions?

Introduction: The emergence of the Zika virus (ZIKV) in Latin America in 2015-2016 led to an expeditious search for vaccine candidates, with a DNA-based candidate having progressed to Phase II. However, several features of ZIKV infection and epidemiology are not understood, which may be key to maximizing efficacy and ensuring safety of ZIKV vaccines. Areas covered: Conceivable problems related to vaccine development and policy include: (1) paucity of diagnostics to satisfactorily discriminate between past ZIKV and dengue virus (DENV) exposure; (2) insufficient knowledge of the mechanisms of ZIKV neurovirulence, amongst other unknowns in the biology of this infection, is particularly relevant from a vaccine safety perspective; and (3) the potential for disease enhancement, as observed with DENV infection and vaccine. Expert opinion: Vaccine candidates that entered phase I/II trials have demonstrated protection in naïve animal models, while ZIKV epidemics occurred in populations that had encountered DENV before. The resulting cross-reactive antibodies pose problems for reliable serologic diagnostic assays, and for the potential of disease enhancement. The alleged neurological complications also warrant further exploration in order to reassure regulators of the safety profile of these vaccines in target populations. These research aspects should be an integral part of the efforts to develop a vaccine.</p

Naturally mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Staphylococcus aureusis a major bacterial pathogen, which causes severe blood and tissue infections that frequently emerge by autoinfection with asymptomatically carried nose and skin populations. However, recent studies report that bloodstream isolates differ systematically from those found in the nose and skin, exhibiting reduced toxicity toward leukocytes. In two patients, an attenuated toxicity bloodstream infection evolved from an asymptomatically carried high-toxicity nasal strain by loss-of-function mutations in the gene encoding the transcription factor repressor of surface proteins (rsp). Here, we report that rsp knockout mutants lead to global transcriptional and proteomic reprofiling, and they exhibit the greatest signal in a genome-wide screen for genes influencing S. aureus survival in human cells. This effect is likely to be mediated in part via SSR42, a long-noncoding RNA. We show that rsp controls SSR42 expression, is induced by hydrogen peroxide, and is required for normal cytotoxicity and hemolytic activity. Rsp inactivation in laboratory- and bacteremia derived mutants attenuates toxin production, but up-regulates other immune subversion proteins and reduces lethality during experimental infection. Crucially, inactivation of rsp preserves bacterial dissemination, because it affects neither formation of deep abscesses in mice nor survival in human blood. Thus, we have identified a spontaneously evolving, attenuated-cytotoxicity, non hemolytic S. aureus phenotype, controlled by a pleiotropic transcriptional regulator/noncoding RNA virulence regulatory system, capable of causing S. aureus bloodstream infections. Such a phenotype could promote deep infection with limited early clinical manifestations, raising concerns that bacterial evolution within the human body may contribute to severe infection