The pertussis epidemic: informing strategies for prevention of severe disease.

To assess the impact of Bordetella pertussis infections in South Australia during an epidemic and determine vulnerable populations, data from notification reports for pertussis cases occurring between July 2008 and December 2009 were reviewed to determine the distribution of disease according to specific risk factors and examine associations with hospitalizations. Although the majority (66%) of the 6230 notifications for pertussis occurred in adults aged >24 years, the highest notification and hospitalization rate occurred in infants aged <1 year. For these infants, factors associated with hospitalization included being aged <2 months [relative risk (RR) 2·3, 95% confidence interval (CI) 1·60-3·32], Indigenous ethnicity (RR 1·7, 95% CI 1·03-2·83) and receiving fewer than two doses of pertussis vaccine (RR 4·1, 95% CI 1·37-12·11). A combination of strategies aimed at improving direct protection for newborns, vaccination for the elderly, and reducing transmission from close contacts of infants are required for prevention of severe pertussis disease.

Safety of meningococcal B vaccine (4CMenB) in adolescents in Australia.

BACKGROUND: Four-component meningococcal B (4CMenB) vaccine is licensed in many countries but has had limited use in adolescents despite this age group being at increased risk of meningococcal disease. OBJECTIVES: To assess the safety profile of two doses of 4CMenB in adolescents. METHODS: Cluster randomised controlled trial of senior school students in South Australia (SA) with participating schools randomised to intervention (4CMenB) or control. Vaccine safety was monitored using the South Australian Vaccine Safety Surveillance System (SAVSS), a spontaneous reporting system for adverse events following immunisation (AEFI) with enhanced follow-up of AEFI. RESULTS: 58,637 doses of 4CMenB vaccine were administered to 30,522 students (median age 16 years) during 2017-2018. Of 18,348 and 12,174 students vaccinated in 2017 and 2018, 97.3% and 84.3%, respectively, received both scheduled doses (N = 28,115). 193 AEFI in 187 students were reported with a reporting rate of 0.32% (95%CI: 0.28-0.39%). Seventy individuals sought medical review, including nine serious adverse events. 98% (166/169) of those who were contactable for AEFI follow-up (87.6% 169/193) reported resolution of the event. Most common AEFI were injection site reaction (126/193), headache (99/193) and nausea (61/193). AEFI were more frequently reported in females (aOR = 1.409 (95%CI: 1.002, 1.980)), schools with high level of educational advantage (adjusted Odds Ratio (aOR) = 1.515 (95%CI: 1.005, 2.284)), following first dose (aOR = 1.619 (95%CI: 1.168, 2.244)), and in 2017 (aOR = 1.437 (95%CI: 1.001, 2.064)). Reported AEFI declined with increasing age (aOR = 0.771 (95%CI: 0.673, 0.883)). CONCLUSION: In this largest post-licensure use of 4CMenB in adolescents, the low AEFI reporting rate provides real-world evidence of 4CMenB safety in this age group. (ClinicalTrials.gov number: NCT03089086).

Adolescent, parent and societal preferences and willingness to pay for meningococcal B vaccine: A Discrete Choice Experiment.

OBJECTIVE: Meningococcal B (MenB) vaccines have been licensed in many countries with private purchase the only option until recently, when a funded programme was introduced in the UK. The aim of this study was to explore adolescent/parental values for a variety of salient vaccine attributes (cost, effectiveness, side effect profile) to assess preferences and willingness-to-pay (WTP) for a MenB vaccine. METHODOLOGY: A national cross-sectional population study was conducted in Australia using Discrete Choice Experiment methodology to assess adolescent/parent/adult preferences for attributes related to MenB vaccine. RESULTS: 2003 adults and 502 adolescents completed the survey in 2013. The majority of participants were willing to be vaccinated with MenB vaccine with vaccination opt-out chosen by 11.9% of adolescents and parents, and 18.2% of non-parent adults. A mixed logit regression model examining adolescent/adult preferences indicated consistent findings; the higher the effectiveness, the longer the duration of protection, the less chance of adverse events and the lower the cost, the more likely respondents were to agree to vaccination. For an ideal MenB vaccine, including the most favoured level of each attribute summed together (90% effectiveness, 10 year duration, 1 injection, no adverse events) adolescents would pay AU$251.60 and parents AU$295.10. Adolescents and parents would pay AU$90.70 or AU$127.20 for 90% vaccine effectiveness vs AU$18.50 or AU$16.70 for 70% effectiveness and would want to be financially compensated for 50% effectiveness; pay AU$63.30 or AU$76.40 for 10 years protection; and pay AU$48.50 or AU$49.20 for no vaccine related adverse events. A slight fever post vaccination was a preferred choice with parents and adolescents willing to pay AU$9.60 or AU$12.30 for this attribute. CONCLUSIONS: Vaccine effectiveness, adverse events and duration of immunity are important drivers for parental and adolescent decisions about WTP for MenB vaccine and should be included in discussions on the benefits, risks and cost.

Maternal uptake of pertussis cocooning strategy and other pregnancy related recommended immunizations.

Maternal immunization is an important strategy to prevent severe morbidity and mortality in mothers and their offspring. This study aimed to identify whether new parents were following immunization recommendations prior to pregnancy, during pregnancy, and postnatally. A cross-sectional survey was conducted by a questionnaire administered antenatally to pregnant women attending a maternity hospital with a follow-up telephone interview at 8-10 weeks post-delivery. Factors associated with uptake of pertussis vaccination within the previous 5 y or postnatally and influenza vaccination during pregnancy were explored using log binomial regression models. A total of 297 pregnant women completed the questionnaire. For influenza vaccine, 20.3% were immunized during pregnancy and 3.0% postnatally. For pertussis vaccine, 13.1% were vaccinated within 5 y prior to pregnancy and 31 women received the vaccine postnatally, 16 (51.6%) received the vaccine >4 weeks after delivery. Receiving a recommendation from a healthcare provider (HCP) was an independent predictor for receipt of both pertussis (RR 2.07, p < 0.001) and influenza vaccine (RR 2.26, p = 0.001). Non-English speaking mothers were significantly less likely to have received pertussis vaccination prior to pregnancy or postnatally (RR 0.24, p = 0.011). Multiparous pregnant women were less likely to have received an influenza vaccine during their current pregnancy (p = 0.015). Uptake of pregnancy related immunization is low and likely due to poor knowledge of availability, language barriers and lack of recommendations from HCPs. Strategies to improve maternal vaccine uptake should include education about recommended vaccines for both HCPs and parents and written information in a variety of languages.

alpha-MSH can control the essential cofactor 6-tetrahydrobiopterin in melanogenesis.

In the human epidermis both keratinocytes and melanocytes express POMC m-RNA. Immunohistochemical studies of both cell types demonstrate significantly higher levels of alpha-MSH in melanocytes than in keratinocytes. Both cell types also hold the full capacity for de novo synthesis/recycling of the essential cofactor (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH4). 6BH4 is critical for the hydroxylation of the aromatic amino acids L-phenylalanine, L-tyrosine, and L-tryptophan, for nitric oxide production and in various immune modulatory processes. Recently it was shown that tyrosinase activity is regulated by 6BH4 through a specific allosteric inhibition. The tyrosinase/6BH4 inhibition can be activated by 1:1 complex formation between 6BH4 and alpha-MSH, but an excess of alpha-MSH over 6BH4 can inhibit tyrosinase due to complex formation by tyr2 in the alpha-MSH sequence. In both melanocytes and keratinocytes 6BH4 controls the L-tyrosine supply via phenylalanine hydroxylase (PAH). Recently we were able to show that the cellular uptake of L-phenylalanine and its intracellular turnover to L-tyrosine is crucial for melanogenesis. alpha-MSH can promote the production of L-tyrosine via PAH due to activation of the PAH tetramer to the more active dimer by removing 6BH4 from the regulatory binding domain on the enzyme. In conclusion, alpha-MSH can control (1) intracellular L-tyrosine formation from L-phenylalanine in both melanocytes and keratinocytes, and (2) tyrosinase activity, directly, in melanocytes.

A bivalent Neisseria meningitidis recombinant lipidated factor H binding protein vaccine in young adults: results of a randomised, controlled, dose-escalation phase 1 trial.

Neisseria meningitidis is a leading cause of meningitis and septicaemia, but a broadly-protective vaccine against endemic serogroup B disease is not licensed and available. The conserved, outer-membrane lipoprotein factor H binding protein (fHBP, also known as LP2086) is expressed as one of two subfamily variants in virtually all meningococci. This study investigated the safety, tolerability, and immunogenicity of a recombinant-expressed bivalent fHBP (r-fHBP) vaccine in healthy adults. Participants (N=103) aged 18-25 years were recruited into three ascending dose level cohorts of 20, 60, and 200µg of a bivalent r-fHBP vaccine formulation and randomised to receive vaccine or placebo at 0, 1, and 6 months. The vaccine was well tolerated. Geometric mean titres (GMTs) for r-fHBP subfamily-specific IgG antibodies increased 19-168-fold from pre-vaccination to post-dose 2 in a dose level-dependent manner. In addition, robust serum bactericidal assay using human complement (hSBA) responses for strains expressing both homologous and heterologous fHBP variants were observed. After three vaccinations, 16-52% of the placebo group and 47-90%, 75-100%, and 88-100%, of the 20, 60, and 200µg dose levels, respectively, had seroprotective (≥ 1:4) hSBA titres against six serogroup B strains. The bivalent r-fHBP vaccine was well tolerated and induced robust bactericidal activity against six diverse serogroup B strains in young adults at the 60 and 200µg dose levels.

In vivo and in vitro evidence for hydrogen peroxide (H2O2) accumulation in the epidermis of patients with vitiligo and its successful removal by a UVB-activated pseudocatalase.

To date there is compelling in vitro and in vivo evidence for epidermal H2O2 accumulation in vitiligo. This paper reviews the literature and presents new data on oxidative stress in the epidermal compartment of this disorder. Elevated H2O2 levels can be demonstrated in vivo in patients compared with healthy controls by utilizing Fourier-Transform Raman spectroscopy. H2O2 accumulation is associated with low epidermal catalase levels. So far, four potential sources for epidermal H2O2 generation in vitiligo have been identified: (i) perturbed (6R)-L-erythro 5,6,7,8 tetrahydrobiopterin (6BH4) de novo synthesis/recycling/regulation; (ii) impaired catecholamine synthesis with increased monoamine oxidase A activities; (iii) low glutathione peroxidase activities; and (iv) "oxygen burst" via NADPH oxidase from a cellular infiltrate. H2O2 overproduction can cause inactivation of catalase as well as vacuolation in epidermal melanocytes and keratinocytes. Vacuolation was also observed in vitro in melanocytes established from lesional and nonlesional epidermis of patients (n = 10) but was reversible upon addition of catalase. H2O2 can directly oxidize 6BH4 to 6-biopterin, which is cytotoxic to melanocytes in vitro. Therefore, we substituted the impaired catalase with a "pseudocatalase". Pseudocatalase is a bis-manganese III-EDTA-(HCO3-)2 complex activated by UVB or natural sun. This complex has been used in a pilot study on 33 patients, showing remarkable repigmentation even in long lasting disease. Currently this approach is under worldwide clinical investigation in an open trial. In conclusion, there are several lines of evidence that the entire epidermis of patients with vitiligo is involved in the disease process and that correction of the epidermal redox status is mandatory for repigmentation.