Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case–control study
Abstract Background It has been proposed that childhood vaccines in high-mortality populations may have substantial impacts on mortality rates that are not explained by the prevention of targeted diseases, nor conversely by typical expected adverse reactions to the vaccines, and that these non-speci...
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| Format: | Article |
| Language: | English |
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BMC
2022-10-01
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| Series: | BMC Veterinary Research |
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| Online Access: | https://doi.org/10.1186/s12917-022-03455-6 |
| _version_ | 1811236378846953472 |
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| author | Darryn L. Knobel Anne Conan Felix N. Toka Sintayehu M. Arega Charles Byaruhanga Eric Ogola Erick M. O. Muok Jan E. Crafford Andrew L. Leisewitz Melvyn Quan Mary Anna Thrall |
| author_facet | Darryn L. Knobel Anne Conan Felix N. Toka Sintayehu M. Arega Charles Byaruhanga Eric Ogola Erick M. O. Muok Jan E. Crafford Andrew L. Leisewitz Melvyn Quan Mary Anna Thrall |
| author_sort | Darryn L. Knobel |
| collection | DOAJ |
| description | Abstract Background It has been proposed that childhood vaccines in high-mortality populations may have substantial impacts on mortality rates that are not explained by the prevention of targeted diseases, nor conversely by typical expected adverse reactions to the vaccines, and that these non-specific effects (NSEs) are generally more pronounced in females. The existence of these effects, and any implications for the development of vaccines and the design of vaccination programs to enhance safety, remain controversial. One area of controversy is the reported association of non-live vaccines with increased female mortality. In a previous randomized controlled trial (RCT), we observed that non-live alum-adjuvanted animal rabies vaccine (ARV) was associated with increased female but not male mortality in young, free-roaming dogs. Conversely, non-live non-adjuvanted human rabies vaccine (NRV) has been associated with beneficial non-specific effects in children. Alum adjuvant has been shown to suppress Th1 responses to pathogens, leading us to hypothesize that alum-adjuvanted rabies vaccine in young dogs has a detrimental effect on female survival by modulating the immune response to infectious and/or parasitic diseases. In this paper, we present the protocol of a 3-arm RCT comparing the effect of alum-adjuvanted rabies vaccine, non-adjuvanted rabies vaccine and placebo on all-cause mortality in an owned, free-roaming dog population, with causal mediation analysis of the RCT and a nested case–control study to test this hypothesis. Methods Randomised controlled trial with a nested case–control study. Discussion We expect that, among the placebo group, males will have higher mortality caused by higher pathogen loads and more severe disease, as determined by haematological parameters and inflammatory biomarkers. Among females, we expect that there will be no difference in mortality between the NRV and placebo groups, but that the ARV group will have higher mortality, again mediated by higher pathogen loads and more severe disease. We anticipate that these changes are preceded by shifts in key serum cytokine concentrations towards an anti-inflammatory immune response in females. If confirmed, these results will provide a rational basis for mitigation of detrimental NSEs of non-live vaccines in high-mortality populations. |
| first_indexed | 2024-04-12T12:08:15Z |
| format | Article |
| id | doaj.art-8d4fe3f552004af69e09dc76b89c3fda |
| institution | Directory Open Access Journal |
| issn | 1746-6148 |
| language | English |
| last_indexed | 2024-04-12T12:08:15Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Veterinary Research |
| spelling | doaj.art-8d4fe3f552004af69e09dc76b89c3fda2022-12-22T03:33:39ZengBMCBMC Veterinary Research1746-61482022-10-0118111410.1186/s12917-022-03455-6Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case–control studyDarryn L. Knobel0Anne Conan1Felix N. Toka2Sintayehu M. Arega3Charles Byaruhanga4Eric Ogola5Erick M. O. Muok6Jan E. Crafford7Andrew L. Leisewitz8Melvyn Quan9Mary Anna Thrall10Department of Biomedical Sciences, Ross University School of Veterinary MedicineCenter for Applied One Health Research and Policy Advice, City University of Hong KongDepartment of Biomedical Sciences, Ross University School of Veterinary MedicineDepartment of Public and Community Health, Jaramogi Oginga Odinga University of Science and TechnologyDepartment of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of PretoriaDepartment of Public and Community Health, Jaramogi Oginga Odinga University of Science and TechnologyCentre for Global Health Research, Kenya Medical Research InstituteDepartment of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of PretoriaDepartment of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of PretoriaDepartment of Veterinary Tropical Diseases, Faculty of Veterinary Science, University of PretoriaDepartment of Biomedical Sciences, Ross University School of Veterinary MedicineAbstract Background It has been proposed that childhood vaccines in high-mortality populations may have substantial impacts on mortality rates that are not explained by the prevention of targeted diseases, nor conversely by typical expected adverse reactions to the vaccines, and that these non-specific effects (NSEs) are generally more pronounced in females. The existence of these effects, and any implications for the development of vaccines and the design of vaccination programs to enhance safety, remain controversial. One area of controversy is the reported association of non-live vaccines with increased female mortality. In a previous randomized controlled trial (RCT), we observed that non-live alum-adjuvanted animal rabies vaccine (ARV) was associated with increased female but not male mortality in young, free-roaming dogs. Conversely, non-live non-adjuvanted human rabies vaccine (NRV) has been associated with beneficial non-specific effects in children. Alum adjuvant has been shown to suppress Th1 responses to pathogens, leading us to hypothesize that alum-adjuvanted rabies vaccine in young dogs has a detrimental effect on female survival by modulating the immune response to infectious and/or parasitic diseases. In this paper, we present the protocol of a 3-arm RCT comparing the effect of alum-adjuvanted rabies vaccine, non-adjuvanted rabies vaccine and placebo on all-cause mortality in an owned, free-roaming dog population, with causal mediation analysis of the RCT and a nested case–control study to test this hypothesis. Methods Randomised controlled trial with a nested case–control study. Discussion We expect that, among the placebo group, males will have higher mortality caused by higher pathogen loads and more severe disease, as determined by haematological parameters and inflammatory biomarkers. Among females, we expect that there will be no difference in mortality between the NRV and placebo groups, but that the ARV group will have higher mortality, again mediated by higher pathogen loads and more severe disease. We anticipate that these changes are preceded by shifts in key serum cytokine concentrations towards an anti-inflammatory immune response in females. If confirmed, these results will provide a rational basis for mitigation of detrimental NSEs of non-live vaccines in high-mortality populations.https://doi.org/10.1186/s12917-022-03455-6Non-specific effectsVaccineSexMortalityRabiesDogs |
| spellingShingle | Darryn L. Knobel Anne Conan Felix N. Toka Sintayehu M. Arega Charles Byaruhanga Eric Ogola Erick M. O. Muok Jan E. Crafford Andrew L. Leisewitz Melvyn Quan Mary Anna Thrall Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case–control study BMC Veterinary Research Non-specific effects Vaccine Sex Mortality Rabies Dogs |
| title | Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case–control study |
| title_full | Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case–control study |
| title_fullStr | Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case–control study |
| title_full_unstemmed | Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case–control study |
| title_short | Sex-differential non-specific effects of adjuvanted and non-adjuvanted rabies vaccines versus placebo on all-cause mortality in dogs (NERVE-Dog study): a study protocol for a randomized controlled trial with a nested case–control study |
| title_sort | sex differential non specific effects of adjuvanted and non adjuvanted rabies vaccines versus placebo on all cause mortality in dogs nerve dog study a study protocol for a randomized controlled trial with a nested case control study |
| topic | Non-specific effects Vaccine Sex Mortality Rabies Dogs |
| url | https://doi.org/10.1186/s12917-022-03455-6 |
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