Prime-Pull Immunization with a Bivalent M-Protein and Spy-CEP Peptide Vaccine Adjuvanted with CAF®01 Liposomes Induces Both Mucosal and Peripheral Protection from covR/S Mutant Streptococcus pyogenes.

Infections with Streptococcus pyogenes and their sequelae are responsible for an estimated 18 million cases of serious disease with >700 million new primary cases and 500,000 deaths per year. Despite the burden of disease, there is currently no vaccine available for this organism. Here, we define a combination vaccine P*17/K4S2 comprising of 20-mer B-cell peptide epitopes, p*17 (a mutant derived from the highly conserved C3-repeat region of the M-protein), and K4S2 (derived from the streptococcal anti-neutrophil factor, Spy-CEP). The peptides are chemically conjugated to either diphtheria toxoid (DT) or a nontoxic mutant form of diphtheria toxin, CRM197. We demonstrate that a prime-pull immunization regimen involving two intramuscular inoculations with P*17/K4S2 adjuvanted with a two-component liposomal adjuvant system (CAF01; developed by Statens Serum Institut [SSI], Denmark), followed by an intranasal inoculation of unadjuvanted vaccine (in Tris) induces peptide- and S. pyogenes-binding antibodies and protects from mucosal and skin infection with hypervirulent covR/S mutant organisms. Prior vaccination with DT does not diminish the response to the conjugate peptide vaccines. Detailed Good Laboratory Practice (GLP) toxicological evaluation in male and female rats did not reveal any gross or histopathological adverse effects.IMPORTANCE A vaccine to control S. pyogenes infection is desperately warranted. S. pyogenes colonizes the upper respiratory tract (URT) and skin, from where it can progress to invasive and immune-mediated diseases. Global mortality estimates for S. pyogenes-associated diseases exceeds 500,000 deaths per year. S. pyogenes utilizes antigenic variation as a defense mechanism to circumvent host immune responses and thus a successful vaccine needs to provide strain-transcending and multicompartment (mucosal and skin) immunity. By defining highly conserved and protective epitopes from two critical virulence factors (M-protein and Spy-CEP) and combining them with a potent immunostimulant, CAF®01, we are addressing an unmet clinical need for a mucosally and skin-active subunit vaccine. We demonstrate that prime-pull immunization (2× intramuscular injections followed by intranasal immunization) promotes high sustained antibody levels in the airway mucosa and serum and protects against URT and invasive disease.

Effects of parenting interventions for mothers with depressive symptoms and an infant: systematic review and meta-analysis.

BACKGROUND: Postpartum depression is common in the perinatal period and poses a risk for the development of the infant and the mother-infant relationship. Infancy is a critical developmental period of life and supportive parenting is crucial for healthy development, however, the effects of interventions aimed at improving parenting among mothers with depression are uncertain. AIMS: To assess the effects of parenting interventions on parent-child relationship and child development among mothers with depressive symptoms with 0-12-month-old infants. METHOD: We conducted a systematic review with the inclusion criteria: (a) randomised controlled trials of structured psychosocial parenting interventions for women with depressive symptoms and a child aged 0-12 months in Western Organisation for Economic Co-operation and Development countries, (b) minimum three sessions with at least half of these delivered postnatally and (c) outcomes relating to the parent-child-relationship and/or child development. Publications were extracted from 10 databases in September 2018 and supplemented with grey search and hand search. We assessed risk of bias, calculated effect sizes and conducted meta-analysis. RESULTS: Eight papers representing seven trials were included. We conducted meta-analysis on the post-intervention parent-child relationship. The analysis included six studies and showed no significant effect. For individual study outcomes, no significant effects on the majority of both the parent-child relationship and child development outcomes were reported. CONCLUSIONS: No evidence of the effect of parenting interventions for mothers with depressive symptoms was found on the parent-child relationship and child development. Larger studies with follow-up assessments are needed, and future reviews should examine the effects in non-Western countries.

Effects of parenting interventions for at-risk parents with infants: a systematic review and meta-analyses.

OBJECTIVES: Infancy is a critical stage of life, and a secure relationship with caring and responsive caregivers is crucial for healthy infant development. Early parenting interventions aim to support families in which infants are at risk of developmental harm. Our objective is to systematically review the effects of parenting interventions on child development and on parent-child relationship for at-risk families with infants aged 0-12 months. DESIGN: This is a systematic review and meta-analyses. We extracted publications from 10 databases in June 2013, January 2015 and June 2016, and supplemented with grey literature and hand search. We assessed risk of bias, calculated effect sizes and conducted meta-analyses. INCLUSION CRITERIA: (1) Randomised controlled trials of structured psychosocial interventions offered to at-risk families with infants aged 0-12 months in Western Organisation for Economic Co-operation and Development (OECD) countries, (2) interventions with a minimum of three sessions and at least half of these delivered postnatally and (3) outcomes reported for child development or parent-child relationship. RESULTS: Sixteen studies were included. Meta-analyses were conducted on seven outcomes represented in 13 studies. Parenting interventions significantly improved child behaviour (d=0.14; 95% CI 0.03 to 0.26), parent-child relationship (d=0.44; 95% CI 0.09 to 0.80) and maternal sensitivity (d=0.46; 95% CI 0.26 to 0.65) postintervention. There were no significant effects on cognitive development (d=0.13; 95% CI -0.08 to 0.41), internalising behaviour (d=0.16; 95% CI -0.03 to 0.33) or externalising behaviour (d=0.16; 95% CI -0.01 to 0.30) post-intervention. At long-term follow-up we found no significant effect on child behaviour (d=0.15; 95% CI -0.03 to 0.31). CONCLUSIONS: Interventions offered to at-risk families in the first year of the child's life appear to improve child behaviour, parent-child relationship and maternal sensitivity post-intervention, but not child cognitive development and internalising or externalising behaviour. Future studies should incorporate follow-up assessments to examine long-term effects of early interventions.