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      Nonspecific Effects of Oral Polio Vaccine on Diarrheal Burden and Etiology Among Bangladeshi Infants

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          Main point

          Oral Polio Virus may cause nonspecific reductions in mortality by reducing etiology-specific diarrheal burden, specifically the number of days with diarrhea. This is likely driven by reductions in bacterial—especially Campylobacter, Shigella—diarrhea. Similar off-target effects were not identified for rotavirus vaccine.

          Abstract

          Background.

          As the global polio eradication initiative prepares to cease use of oral polio vaccine (OPV) in 2020, there is increasing interest in understanding if oral vaccination provides non-specific immunity to other infections so that the consequences of this transition can be effectively planned for and mitigated.

          Methods.

          Data were collected from infants in an urban slum in Bangladesh (Mirpur, Dhaka) as part of the performance of rotavirus and oral polio vaccines in developing countries (PROVIDE) study. Following vaccination with trivalent oral polio vaccine (tOPV) at 6, 10, and 14 weeks, infants were randomly assigned to receive tOPV (n = 315) or inactivated polio vaccine (IPV) (n = 299) at 39 weeks. Episodes of diarrhea were documented through clinic visits and twice-weekly house visits through 52 weeks. In sum, 14 pathogens associated with diarrhea were analyzed with TaqMan Array Cards.

          Results.

          Although the proportion of children experiencing diarrhea was not different between the tOPV and IPV groups ( P = .18), the number of days with diarrhea ( P = .0037) and the number of separate diarrheal episodes ( P = .054) trended lower in the OPV arm. Etiological analysis revealed that male tOPV recipients were less likely to have diarrhea of bacterial etiology ( P = .0099) compared to male IPV recipients but equally likely to experience diarrhea due to viruses ( P = .57) or protozoa ( P = .14). Among the 6 bacterial enteric pathogens tested, only Campylobacter jejuni/ coli detection was significantly reduced in the OPV arm ( P = .0048).

          Conclusions.

          Our results suggest that OPV may cause nonspecific reductions in mortality, as has been studied elsewhere, by reducing etiology-specific diarrheal burden. This is likely driven by reductions in bacterial diarrhea. Further study of nonspecific OPV effects before global cessation is supported.

          Clinical Trials Registration.

          NCT01375647.

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          Most cited references18

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          Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes.

          Immunological memory in vertebrates is often exclusively attributed to T and B cell function. Recently it was proposed that the enhanced and sustained innate immune responses following initial infectious exposure may also afford protection against reinfection. Testing this concept of "trained immunity," we show that mice lacking functional T and B lymphocytes are protected against reinfection with Candida albicans in a monocyte-dependent manner. C. albicans and fungal cell wall β-glucans induced functional reprogramming of monocytes, leading to enhanced cytokine production in vivo and in vitro. The training required the β-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. Monocyte training by β-glucans was associated with stable changes in histone trimethylation at H3K4, which suggests the involvement of epigenetic mechanisms in this phenomenon. The functional reprogramming of monocytes, reminiscent of similar NK cell properties, supports the concept of "trained immunity" and may be employed for the design of improved vaccination strategies. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Sex Differences in Pediatric Infectious Diseases

            The success of the immune response is finely balanced between, on the one hand, the need to engage vigorously with, and clear, certain pathogens; and, on the other, the requirement to minimize immunopathology and autoimmunity. Distinct immune strategies to achieve this balance have evolved in females and males and also in infancy through to adulthood. Sex differences in outcome from a range of infectious diseases can be identified from as early as fetal life, such as in congenital cytomegalovirus infection. The impact of sex hormones on the T-helper 1/T-helper 2 cytokine balance has been proposed to explain the higher severity of most infectious diseases in males. In the minority where greater morbidity and mortality is observed in females, this is hypothesized to arise because of greater immunopathology and/or autoimmunity. However, a number of unexplained exceptions to this rule are described. Studies that have actually measured the sex differences in children in the immune responses to infectious diseases and that would further test these hypotheses, are relatively scarce.
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              Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial

              Objective To examine in a randomised trial whether a 25% difference in mortality exists between 4.5 months and 3 years of age for children given two standard doses of Edmonston-Zagreb measles vaccines at 4.5 and 9 months of age compared with those given one dose of measles vaccine at 9 months of age (current policy). Design Randomised controlled trial. Setting The Bandim Health Project, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area. Participants 6648 children aged 4.5 months of age who had received three doses of diphtheria-tetanus-pertussis vaccine at least four weeks before enrolment. A large proportion of the children (80%) had previously taken part in randomised trials of neonatal vitamin A supplementation. Intervention Children were randomised to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months of age (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months of age (group C). Main outcome measure Mortality rate ratio between 4.5 and 36 months of age for group A compared with groups B and C. Secondary outcomes tested the hypothesis that the beneficial effect was stronger in the 4.5 to 9 months age group, in girls, and in the dry season, but the study was not powered to test whether effects differed significantly between subgroups. Results In the intention to treat analysis of mortality between 4.5 and 36 months of age the mortality rate ratio of children who received two doses of Edmonston-Zagreb vaccine at 4.5 and 9 months of age compared with those who received a single dose of Edmonston-Zagreb vaccine or Schwarz vaccine at 9 months of age was 0.78 (95% confidence interval 0.59 to 1.05). In the analyses of secondary outcomes, the intention to treat mortality rate ratio was 0.67 (0.38 to 1.19) between 4.5 and 9 months and 0.83 (0.83 to 1.16) between 9 and 36 months of age. The effect on mortality between 4.5 and 36 months of age was significant for girls (intention to treat mortality rate ratio 0.64 (0.42 to 0.98)), although this was not significantly different from the effect in boys (0.95 (0.64 to 1.42)) (interaction test, P=0.18). The effect did not differ between the dry season and the rainy season. As neonatal vitamin A supplementation is not WHO policy, the analyses were done separately for the 3402 children who did not receive neonatal vitamin A. In these children, the two dose Edmonston-Zagreb measles vaccine schedule was associated with a significantly lower mortality between 4.5 and 36 months of age (intention to treat mortality rate ratio 0.59 (0.39 to 0.89)). The effect was again significant for girls but not statistically significant from the effect in boys. When measles cases were censored, the intention to treat mortality rate ratio was 0.65 (0.43 to 0.99). Conclusions Although the overall effect did not reach statistical significance, the results may indicate that a two dose schedule with Edmonston-Zagreb measles vaccine given at 4.5 and 9 months of age has beneficial non-specific effects on children’s survival, particularly for girls and for children who have not received neonatal vitamin A. This should be tested in future studies in different locations. Trial registration Clinical trials NCT00168558.
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                Author and article information

                Journal
                Clin Infect Dis
                Clin. Infect. Dis
                cid
                Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
                Oxford University Press (US )
                1058-4838
                1537-6591
                01 August 2017
                24 April 2017
                24 April 2017
                : 65
                : 3
                : 414-419
                Affiliations
                [1 ] Center for World Health, David Geffen School of Medicine at University of California, Los Angeles (UCLA) ;
                [2 ] Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia , Charlottesville;
                [3 ] Vaccine Testing Center and Unit of Infectious Diseases, Department of Medicine, University of Vermont College of Medicine , Burlington;
                [4 ] Centers for Disease Control and Prevention , Atlanta, Georgia;
                [5 ] Center for Vaccine Science and Parasitology Lab, International Centre for Diarrhoeal Disease Research , Bangladesh, Dhaka
                Author notes

                Correspondence: A. Upfill-Brown, Center for World Health, David Geffen School of Medicine at UCLA, Los Angeles, CA 99095 ( aupfillbrown@ 123456mednet.ucla.edu ).

                Article
                cix354
                10.1093/cid/cix354
                5848225
                28444240
                8968489e-a0de-4719-bb96-c4abd8f75b72
                © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 05 January 2017
                : 20 April 2017
                Page count
                Pages: 6
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: R501 A1043596
                Categories
                Major Article

                Infectious disease & Microbiology
                opv,vaccines,enteropathogens,diarrhea,cross-protection
                Infectious disease & Microbiology
                opv, vaccines, enteropathogens, diarrhea, cross-protection

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