Non-specific effects of rabies vaccine on the incidence of common infectious disease episodes: study protocol for a randomized controlled trial.

BACKGROUND: Vaccines may cause non-specific effects (NSEs) on morbidity and mortality through immune-mediated mechanisms that are not explained by the prevention of the targeted disease. Much of the evidence for NSEs comes from observational studies with a high risk of bias, and there is a clear need for new data from randomized controlled trials. Recently, it was proposed that rabies vaccine has protective NSEs in people and in animals. The aim of the proposed study is to determine whether rabies vaccine reduces the incidence rate of episodes of common infectious disease syndromes in a population of veterinary students on the island of St. Kitts. METHODS: The trial design is a single-site, two-arm, parallel-group, participant-blinded, randomized, placebo-controlled, two-sided comparative study, with an internal pilot study for blinded sample size re-estimation. Allocation to study arm is by block randomization stratified by sex within cohort with a 1:1 allocation ratio. The primary study outcome is the number of new weekly episodes of common infectious diseases including respiratory, diarrheal and febrile illnesses. A vaccine immunogenicity ancillary study is planned. DISCUSSION: Demonstration of a non-specific protective effect of rabies vaccine against unrelated respiratory, gastrointestinal and febrile illnesses would provide supportive evidence for the design of similar studies in children in populations with a high burden of these illnesses. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03656198. Registered on 24 August 2018.

Pneumococcal conjugate vaccine against serotype 3 pneumococcal pneumonia in adults: A systematic review and pooled analysis.

BACKGROUND: Serotype 3 pneumococcal disease has not substantially declined at the population level after the routine introduction of 13-valent pneumococcal conjugate vaccine (PCV13) into pediatric immunization programs across the globe. This epidemiological finding has generated debate regarding the effectiveness of PCV13 against serotype 3 disease. Evaluating PCV13 effectiveness against serotype 3 is especially critical in adults, where serotype 3 makes up an important amount of remaining pneumococcal disease. METHODS: We performed a systematic review of the published literature to assess the direct effectiveness of PCV13 against serotype 3 community-acquired pneumonia (CAP) among adults. We then estimated overall vaccine effectiveness (VE) using a pooled analysis of the individual-level, raw data. RESULTS: Two published studies met inclusion criteria. One was a randomized controlled trial conducted in the Netherlands and published in 2014. The other was a recently-published case-control study conducted in Louisville, Kentucky that used a test-negative design (TND). We also identified a third TND study conducted in Argentina that was recently presented as a conference abstract but is not yet published. All three studies were conducted in adults aged ≥65 years. PCV13 VE against serotype 3 hospitalized CAP was 52.5% (95%CI: 6.2-75.9%) from the pooled analysis of individual-level data from all three studies. Results were similar if the unpublished estimate was excluded (serotype 3 VE = 53.6% [95%CI: 6.7-76.9%]). No heterogeneity was observed. CONCLUSIONS: Currently-available evidence, although limited to three studies, suggests that PCV13 provides direct protection against serotype 3 hospitalized CAP in adults aged ≥65 years.

Multi-site cholera surveillance within the African Cholera Surveillance Network shows endemicity in Mozambique, 2011-2015

Background: Mozambique suffers recurrent annual cholera outbreaks especially during the rainy season between October to March. The African Cholera Surveillance Network (Africhol) was implemented in Mozambique in 2011 to generate accurate detailed surveillance data to support appropriate interventions for cholera control and prevention in the country. Methodology/principal findings: Africhol was implemented in enhanced surveillance zones located in the provinces of Sofala (Beira), Zambézia (District Mocuba), and Cabo Delgado (Pemba City). Data were also analyzed from the three outbreak areas that experienced the greatest number of cases during the time period under observation (in the districts of Cuamba, Montepuez, and Nampula). Rectal swabs were collected from suspected cases for identification of Vibrio cholerae, as well as clinical, behavioral, and socio-demographic variables. We analyzed factors associated with confirmed, hospitalized, and fatal cholera using multivariate logistic regression models. A total of 1,863 suspected cases and 23 deaths (case fatality ratio (CFR), 1.2%) were reported from October 2011 to December 2015. Among these suspected cases, 52.2% were tested of which 23.5% were positive for Vibrio cholerae O1 Ogawa. Risk factors independently associated with the occurrence of confirmed cholera were living in Nampula city district, the year 2014, human immunodeficiency virus infection, and the primary water source for drinking. Conclusions/significance: Cholera was endemic in Mozambique during the study period with a high CFR and identifiable risk factors. The study reinforces the importance of continued cholera surveillance, including a strong laboratory component. The results enhanced our understanding of the need to target priority areas and at-risk populations for interventions including oral cholera vaccine (OCV) use, and assess the impact of prevention and control strategies. Our data were instrumental in informing integrated prevention and control efforts during major cholera outbreaks in recent years.

Association of a genetic variant of carnitine palmitoyltransferase 1A with infections in Alaska Native children.

OBJECTIVE: To evaluate whether the arctic variant (c.1436C→T) of carnitine palmitoyltransferase type 1A (CPT1A) is associated with a higher incidence of adverse health outcomes in Alaska Native infants and children. STUDY DESIGN: We evaluated health measures from birth certificates (n = 605) and Alaska Medicaid billing claims (n = 427) collected from birth to 2.5 years of age for a cohort of Alaska Native infants with known CPT1A genotype. To account for geographic variations in gene distribution and other variables, data also were evaluated in cohorts. RESULTS: When analysis was restricted to residents of nonhub communities in Western and Northern Alaska, children homozygous for the arctic variant experienced more episodes of lower respiratory tract infection than did heterozygous or noncarrier children (5.5 vs 3.7, P = .067) and were more likely to have had otitis media (86% vs 69%, 95% CI 1.4-8.9). Associations were weaker for more homogeneous cohorts. CONCLUSIONS: The association of the arctic variant of CPT1A with infectious disease outcomes in children between birth and 2.5 years of age suggests that this variant may play a role in the historically high incidence of these health outcomes among indigenous Arctic populations; further studies will need to assess if this association was confounded by other risk factors.

Prevalence and distribution of the c.1436C→T sequence variant of carnitine palmitoyltransferase 1A among Alaska Native infants.

OBJECTIVES: To use genotype analysis to determine the prevalence of the c.1436C→T sequence variant in carnitine palmitoyltransferase 1A (CPT1A) among Alaskan infants, and evaluate the sensitivity of newborn screening by tandem mass spectrometry (MS/MS) to identify homozygous infants. STUDY DESIGN: We compared MS/MS and DNA analyses of 2409 newborn blood spots collected over 3 consecutive months. RESULTS: Of 2409 infants, 166 (6.9%) were homozygous for the variant, all but one of whom were of Alaska Native race. None of the homozygous infants was identified by MS/MS on the first newborn screen using a C0/C16 + C18 cutoff of 130. Among 633 Alaska Native infants, 165 (26.1%) were homozygous and 218 (34.4%) were heterozygous for the variant. The prevalence was highest in Alaska's northern/western regions (51.2% of 255 infants homozygous; allele frequency, 0.7). CONCLUSIONS: The CPT1A c.1436C→T variant is prevalent among some Alaska Native peoples, but newborn screening using current MS/MS cutoffs is not an effective means to identify homozygous infants. The clinical consequences of the partial CPT1A deficiency associated with this variant are unknown. If effects are substantial, revision of newborn screening, including Alaska-specific MS/MS cutoffs and confirmatory genotyping, may be needed.

Lack of piped water and sewage services is associated with pediatric lower respiratory tract infection in Alaska.

OBJECTIVES: To determine the association between the high incidence of lower respiratory tract infection (LRI) documented among young Alaskan children and the absence of modern water service (in-home piped water/septic system or water delivered by closed haul truck) found commonly in rural Alaskan communities. STUDY DESIGN: A community-level analysis was performed of all 108 Alaskan communities with at least 15 children <2 years of age enrolled in Medicaid during 1998-2003. Community LRI incidence rates were determined from a Medicaid database with standard LRI billing codes. Potentially confounding community-level demographic variables were obtained, as was availability of water service. RESULTS: During linear regression analysis, the percentage of households with modern water service in a community predicted community-level outpatient (beta = -0.53; P < .001) and inpatient (beta = -0.15; P = .088) LRI incidence rates when controlling for the degree of household crowding, unemployment, adult education, tobacco cigarette use, wood stove use, and poverty. Modest improvements in water service delivery were not shown to be associated with changes in LRI burden. CONCLUSIONS: Lack of modern water service in Alaska is associated with high pediatric LRI incidence. These communities should receive modern water service, but this intervention alone may not dramatically reduce LRI burden.

25-hydroxyvitamin D levels among healthy children in Alaska.

OBJECTIVE: To determine vitamin D levels among children 6 to 23 months old receiving services from Women, Infants, and Children (WIC) programs in Alaska. Study design During 2001 and 2002, we recruited 133 children receiving services at seven WIC clinics, administered a risk factor questionnaire, and collected blood. RESULTS: Fifteen (11%) and 26 (20%) children, respectively, had vitamin D levels <15 (considered abnormal) and 15 to <25 ng/mL (low normal). Compared with other children, children who still breast-fed were more likely to have a vitamin D level <15 ng/mL (relative risk [RR], 12; 95% confidence interval [CI], 3.6-39) or 15 to <25 ng/mL (RR, 3.6; 95% CI, 1.9-6.8) than > or =25 ng/mL. Among 41 still breast-feeding children, 14 (34%) took supplemental vitamins, and six (18%) were reported to have received vitamins every day. CONCLUSIONS: Vitamin D deficiency is prevalent in Alaska. Breast-feeding in the absence of adequate vitamin D supplementation is the greatest risk factor.