Cytomegalovirus is the leading cause of congenital viral disease and the most important opportunistic infection in immunocompromised patients. We have used a mouse experimental infection model (MCMV) to study the genetic parameters of host/virus interaction. Susceptibility to infection with MCMV is controlled by Cmv1, a chromosome 6 locus that regulates natural killer (NK) cell activity against virally infected targets. Here, we use a positional cloning strategy to isolate the gene mutated at the Cmv1 locus. Cmv1 maps within a 0.35-cM interval defined by markers D6Ott8 and D6Ott115, which corresponds to a physical distance of 1.6 Mb (refs. 6-8). A transcript map of the region identified 19 genes, including members of the killer cell lectin-like receptor family a (Klra, formerly Ly49; refs. 9-12), which encode inhibitory or activating NK cell receptors that interact with MHC class I molecules. Klra genes have different copy numbers and genomic organization, and are highly polymorphic among inbred strains, making it difficult to distinguish between normal allelic variants and distinct Klra genes, or possible mutations associated with Cmv1. The recombinant inbred strain BXD-8/Ty (BXD-8; ref. 18), derived from Cmv1r C57BL/6 (B6, resistant) and Cmv1s DBA/2 (susceptible), is of particular interest because it is highly susceptible to MCMV infection despite having a B6 haplotype at Cmv1. We determined that MCMV susceptibility in BXD-8 is associated with the deletion of Klra8 (formerly Ly49h).
Cytomegalovirus is the leading cause of congenital viral disease and the most important opportunistic infection in immunocompromised patients. We have used a mouse experimental infection model (MCMV) to study the genetic parameters of host/virus interaction. Susceptibility to infection with MCMV is controlled by Cmv1, a chromosome 6 locus that regulates natural killer (NK) cell activity against virally infected targets. Here, we use a positional cloning strategy to isolate the gene mutated at the Cmv1 locus. Cmv1 maps within a 0.35-cM interval defined by markers D6Ott8 and D6Ott115, which corresponds to a physical distance of 1.6 Mb (refs. 6-8). A transcript map of the region identified 19 genes, including members of the killer cell lectin-like receptor family a (Klra, formerly Ly49; refs. 9-12), which encode inhibitory or activating NK cell receptors that interact with MHC class I molecules. Klra genes have different copy numbers and genomic organization, and are highly polymorphic among inbred strains, making it difficult to distinguish between normal allelic variants and distinct Klra genes, or possible mutations associated with Cmv1. The recombinant inbred strain BXD-8/Ty (BXD-8; ref. 18), derived from Cmv1r C57BL/6 (B6, resistant) and Cmv1s DBA/2 (susceptible), is of particular interest because it is highly susceptible to MCMV infection despite having a B6 haplotype at Cmv1. We determined that MCMV susceptibility in BXD-8 is associated with the deletion of Klra8 (formerly Ly49h).
BackgroundStudies of vaccine effectiveness (VE) rely on accurate identification of vaccination and cases of vaccine-preventable disease. In practice, diagnostic tests, clinical case definitions and vaccination records often present inaccuracies, leading to biased VE estimates. Previous studies investigated the impact of non-differential disease misclassification on VE estimation.MethodsWe explored, through simulation, the impact of non-differential and differential disease- and exposure misclassification when estimating VE using cohort, case-control, test-negative case-control and case-cohort designs. The impact of misclassification on the estimated VE is demonstrated for VE studies on childhood seasonal influenza and pertussis vaccination. We additionally developed a web-application graphically presenting bias for user-selected parameters.ResultsDepending on the scenario, the misclassification parameters had differing impacts. Decreased exposure specificity had greatest impact for influenza VE estimation when vaccination coverage was low. Decreased exposure sensitivity had greatest impact for pertussis VE estimation for which high vaccination coverage is typically achieved. The impact of the exposure misclassification parameters was found to be more noticeable than that of the disease misclassification parameters. When misclassification is limited, all study designs perform equally. In case of substantial (differential) disease misclassification, the test-negative design performs worse.ConclusionsMisclassification can lead to significant bias in VE estimates and its impact strongly depends on the scenario. We developed a web-application for assessing the potential (joint) impact of possibly differential disease- and exposure misclassification that can be modified by users to their own study scenario. Our results and the simulation tool may be used to guide better design, conduct and interpretation of future VE studies.
Infants are vulnerable to pertussis infection particularly before initiation of pertussis vaccination. Maternal pertussis vaccination during pregnancy has been introduced in a number of countries in order to confer on young infants indirect protection from the disease through transplacental transfer of maternal antibodies. We reviewed the evidence on the immunogenicity and efficacy of maternal pertussis vaccination during pregnancy. A systematic search of PubMed/MEDLINE, EMBASE, Scopus, Cochrane Database of Systematic Reviews, ProQuest, and Science Direct was undertaken to identify studies published between January 1995 and December 2018. This review was not specific to any particular pertussis vaccine but included applicable data on available pertussis vaccines administered to pregnant women. The search identified 40 publications for inclusion in this review. Vaccination during pregnancy elicited robust maternal immune responses against all vaccine antigens and resulted in high placental transfer of pertussis antibodies to the infant that persisted well beyond delivery. Vaccination during the second or early third trimesters was considered ideal for antibody quantity and functionality. Although blunting of immune responses to some antigens in the primary immunization series was documented in neonates born to women vaccinated during pregnancy, there was no apparent adverse effect on vaccine efficacy. Multiple studies conducted in diverse settings have confirmed the effectiveness of maternal pertussis vaccination during pregnancy in preventing pertussis in infants prior to receipt of their first primary vaccine dose and beyond. These findings collectively underscore the value of maternal pertussis vaccination during pregnancy in protecting vulnerable infants too young to be vaccinated.
The WHO recommends vaccination of all children against pertussis. However, newborn infants remain vulnerable to infection. Pertussis vaccination during pregnancy has been introduced in several countries to protect newborns via transplacental transfer of maternal pertussis antibodies to the infant. We reviewed the impact of maternal pertussis vaccination on the health of pregnant women, the developing fetus, and health of the newborn. We searched PubMed/MEDLINE, EMBASE, Scopus (Elsevier), Cochrane Database of Systematic Reviews, ProQuest, and Science Direct to identify studies that assessed the safety of maternal pertussis vaccination. Twenty-seven English language publications published between January 1995 and December 2018 were included in this review. Pregnant women receiving pertussis vaccines did not have increased rates of systemic or local reactions. There were no safety concerns with repeat vaccination with other tetanus-containing vaccines or their concomitant administration with influenza vaccines. Maternal pertussis vaccination did not adversely affect pregnancy, birth or neonatal outcomes. This review confirms the safety of maternal pertussis vaccination during pregnancy.
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