Sex-differential non-specific effects of rabies vaccine in dogs : an extended analysis of a randomized controlled trial in a high-mortality population

Non-live rabies vaccines have been associated with both beneficial and detrimental effects on host population morbidity and mortality rates to unrelated infections in people and animals, and these non-specific effects may differ by sex. Previous animal studies may have been affected by bias, including selection bias due to loss to follow up in randomized controlled trials (RCTs). We previously reported results of an RCT in dogs on the effect of primary rabies vaccine administered at 6 weeks of age on all-cause mortality over a 7-week follow-up period, in a high-mortality population of owned dogs. Here, we report the results from the same trial of a second vaccination at 13 weeks of age, compared to a primary vaccination. Because a relatively high proportion of study subjects (30%) were lost to follow-up in the RCT, we also conducted an analysis to control for possible selection bias over both periods (6 to 13 weeks and 13 to 20 weeks of age). We found that primary rabies vaccination at 6 weeks of age substantially increased the hazard of death from all causes over the next 7 weeks among females (hazard ratio [HR] 2.69, 95% confidence intervals [CI] 1.27–5.69), but not among males (HR 0.91, 95% CI 0.32–2.59). Among survivors, administration of a second dose of rabies vaccine at 13 weeks of age was associated with a decreased hazard of death among males (HR 0.33, 95% CI 0.10–1.02) but not females (HR 1.64, 95% CI 0.59–4.58), when compared to the group receiving their first dose at this age. Based on our causal assumptions, we show that these results were not affected by selection bias. In this high-mortality dog population, receipt of a non-live rabies vaccine substantially affected all-cause mortality rates, with this effect being strongly modified by sex.Ross University School of Veterinary Medicine (RUSVM).http://www.elsevier.com/locate/vaccinehj2023Veterinary Tropical Disease

Effects of gonadectomy on the incidence rate of babesiosis and the risk of severe babesiosis in dogs aged 6 months and older at a veterinary academic hospital in South Africa : a case-control and retrospective cohort study

Gonadectomy in dogs is associated with changes in risks of a variety of non-infectious health conditions, but few studies have examined its effects on infectious disease outcomes. The objectives of our study were to estimate the causal effect of gonadectomy on the incidence rate of babesiosis diagnosis, and on the risk of severe babesiosis in diagnosed cases, in dogs 6 months and older seen at a veterinary academic hospital in South Africa from 2013 through 2020. To estimate the effect of gonadectomy on the incidence rate of babesiosis diagnosis in dogs, we conducted a case-control study with incidence density sampling of dogs seen through the hospital’s primary care service, adjusting for sex, age, breed category and weight. We identified 811 cases and selected 3244 time-matched controls. To estimate the effect of gonadectomy on disease severity in dogs with babesiosis, we conducted a retrospective cohort study among all dogs with a diagnosis of babesiosis (n=923), including these 811 cases and a further 112 referred to the hospital, also adjusting for sex, age, breed category and weight. Gonadectomy substantially reduced the incidence rate of babesiosis (total effect incidence rate ratio [IRR] 0.5; 95 % confidence interval [CI] 0.41–0.60) and the risk of severe babesiosis among diagnosed dogs (total effect risk ratio [RR] 0.72; 95 % CI 0.60–0.86). Tipping point sensitivity analysis shows that these effect estimates are robust to unmeasured confounding bias. There was no evidence for modification of the effect of gonadectomy by sex, with effect estimates qualitatively similar for males and females for both outcomes. Compared to females, males had a higher incidence rate of babesiosis (IRR 1.74; 95 % CI 1.49–2.04) and a higher risk of severe disease (RR 1.12; 95 % CI 0.98–1.28). In conclusion, our study shows a robust protective effect of gonadectomy on the incidence and severity of babesiosis in both male and female dogs 6 months of age and older, and contributes important evidence to the debate on the overall risks and benefits of gonadectomy to dogs in this population.https://www.elsevier.com/locate/prevetmedhj2024Companion Animal Clinical StudiesVeterinary Tropical DiseasesSDG-03:Good heatlh and well-bein

High prevalence of <i>Rickettsia africae</i> variants in <i>Amblyomma variegatum</i> ticks from domestic mammals in rural western Kenya: implications for human health

Tick-borne spotted fever group (SFG) rickettsioses are emerging human diseases caused by obligate intracellular Gram-negative bacteria of the genus Rickettsia. Despite being important causes of systemic febrile illnesses in travelers returning from sub-Saharan Africa, little is known about the reservoir hosts of these pathogens. We conducted surveys for rickettsiae in domestic animals and ticks in a rural setting in western Kenya. Of the 100 serum specimens tested from each species of domestic ruminant 43% of goats, 23% of sheep, and 1% of cattle had immunoglobulin G (IgG) antibodies to the SFG rickettsiae. None of these sera were positive for IgG against typhus group rickettsiae. We detected Rickettsia africae–genotype DNA in 92.6% of adult Amblyomma variegatum ticks collected from domestic ruminants, but found no evidence of the pathogen in blood specimens from cattle, goats, or sheep. Sequencing of a subset of 21 rickettsia-positive ticks revealed R. africae variants in 95.2% (20/21) of ticks tested. Our findings show a high prevalence of R. africae variants in A. variegatum ticks in western Kenya, which may represent a low disease risk for humans. This may provide a possible explanation for the lack of African tick-bite fever cases among febrile patients in Kenya

Molecular detection of zoonotic rickettsiae and Anaplasma spp. in domestic dogs and their ectoparasites in Bushbuckridge, South Africa

Members of the order Rickettsiales are small, obligate intracellular bacteria that are vector-borne and can cause mild to fatal diseases in humans worldwide. There is little information on the zoonotic rickettsial pathogens that may be harbored by dogs from rural localities in South Africa. To characterize rickettsial pathogens infecting dogs, we screened 141 blood samples, 103 ticks, and 43 fleas collected from domestic dogs in Bushbuckridge Municipality, Mpumalanga Province of South Africa, between October 2011 and May 2012 using the reverse line blot (RLB) and Rickettsia genus and species-specific quantitative real-time PCR (qPCR) assays. Results from RLB showed that 49% of blood samples and 30% of tick pools were positive for the genus-specific probes for Ehrlichia/Anaplasma; 16% of the blood samples were positive for Ehrlichia canis. Hemoparasite DNA could not be detected in 36% of blood samples and 30% of tick pools screened. Seven (70%) tick pools and both flea pools were positive for Rickettsia spp; three (30%) tick pools were positive for Rickettsia africae; and both flea pools (100%) were positive for Rickettsia felis. Sequencing confirmed infection with R. africae and Candidatus Rickettsia asemboensis; an R. felis-like organism from one of the R. felis-positive flea pools. Anaplasma sp. South Africa dog strain (closely related to Anaplasma phagocytophilum), A. phagocytophilum, and an Orientia tsutsugamushi-like sequence were identified from blood samples. The detection of emerging zoonotic agents from domestic dogs and their ectoparasites in a rural community in South Africa highlights the potential risk of human infection that may occur with these pathogens.The HDSS-Dogs platform (protocol no. VO33-11) was supported by funding to Darryn Knobel from the Morris Animal Foundation, United States (grant no.D12CA-312). Drs. A.N. Maina and A.L. Richards were supported by funding of the Global Emerging Infections Surveillance and Response System, work unit # A1402.http://online.liebertpub.com/VBZ2017-04-30hb2016Veterinary Tropical Disease

Rabies in Endangered Ethiopian Wolves

With rabies emerging as a particular threat to wild canids, we report on a rabies outbreak in a subpopulation of endangered Ethiopian wolves in the Bale Mountains, Ethiopia, in 2003 and 2004. Parenteral vaccination of wolves was used to manage the outbreak

A One Medicine Mission for an Effective Rabies Therapy

Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome. Systematic clinical research into combination therapies is further hampered by sporadic occurrence of cases. In this Perspective, we examine the case for a One Medicine approach to accelerate development of an effective therapy for rabies through the veterinary care and investigational treatment of naturally infected dogs in appropriate circumstances. We review the pathogenesis of rabies virus in humans and dogs, including recent advances in our understanding of the molecular basis for the severe neurological dysfunction. We propose that four categories of disease process need to be managed in patients: viral propagation, neuronal degeneration, inflammation and systemic compromise. Compassionate critical care and investigational treatment of naturally infected dogs receiving supportive therapy that mimics the human clinical scenario could increase opportunities to study combination therapies that address these processes, and to identify biomarkers for prognosis and therapeutic response. We discuss the safety and ethics of this approach, and introduce the Canine Rabies Treatment Initiative, a non-profit organization with the mission to apply a One Medicine approach to the investigation of diagnostic, prognostic, and therapeutic options for rabies in naturally infected dogs, to accelerate transformation of rabies into a treatable disease for all patients

Rabies vaccination of 6‐week‐old puppies born to immunized mothers: a randomized controlled trial in a high‐mortality population of owned, free‐roaming dogs

To achieve global elimination of human rabies from dogs by 2030, evidence-based strategies for effective dog vaccination are needed. Current guidelines recommend inclusion of dogs younger than 3 months in mass rabies vaccination campaigns, although available vaccines are only recommended for use by manufacturers in older dogs, ostensibly due to concerns over interference of maternally-acquired immunity with immune response to the vaccine. Adverse effects of vaccination in this age group of dogs have also not been adequately assessed under field conditions. In a single-site, owner-blinded, randomized, placebo-controlled trial in puppies born to mothers vaccinated within the previous 18 months in a high-mortality population of owned, free-roaming dogs in South Africa, we assessed immunogenicity and effect on survival to all causes of mortality of a single dose of rabies vaccine administered at 6 weeks of age. We found that puppies did not have appreciable levels of maternally-derived antibodies at 6 weeks of age (geometric mean titer 0.065 IU/mL, 95% CI 0.061–0.069; n = 346), and that 88% (95% CI 80.7–93.3) of puppies vaccinated at 6 weeks had titers ≥0.5 IU/mL 21 days later (n = 117). Although the average effect of vaccination on survival was not statistically significant (hazard ratio [HR] 1.35, 95% CI 0.83–2.18), this effect was modified by sex (p = 0.02), with the HR in females 3.09 (95% CI 1.24–7.69) and the HR in males 0.79 (95% CI 0.41–1.53). We speculate that this effect is related to the observed survival advantage that females had over males in the unvaccinated group (HR 0.27; 95% CI 0.11–0.70), with vaccination eroding this advantage through as-yet-unknown mechanisms.Supplementary Materials: Table S1. Results of sensitivity analysis for survival analysis (6 to 13 weeks of age), considering subjects reported as lost or stolen by owners as dead (n = 22); Table S2. Results of sensitivity analysis for survival analysis (6 to 13 weeks of age), censoring subjects that reportedly died from accidents (n = 5).http://www.mdpi.com/journal/tropicalmedhj2021Companion Animal Clinical StudiesProduction Animal StudiesVeterinary Tropical Disease

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

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.The RCT reported in this publication is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. The NCC component of the protocol is supported by the Morris Animal Foundation.http://www.biomedcentral.com/bmcvetresam2023Companion Animal Clinical StudiesVeterinary Tropical Disease

High Prevalence of Rickettsia africae Variants in Amblyomma variegatum Ticks from Domestic Mammals in Rural Western Kenya: Implications for Human Health

Tick-borne spotted fever group (SFG) rickettsioses are emerging human diseases caused by obligate intracellular Gram-negative bacteria of the genus Rickettsia. Despite being important causes of systemic febrile illnesses in travelers returning from sub-Saharan Africa, little is known about the reservoir hosts of these pathogens. We conducted surveys for rickettsiae in domestic animals and ticks in a rural setting in western Kenya. Of the 100 serum specimens tested from each species of domestic ruminant 43% of goats, 23% of sheep, and 1% of cattle had immunoglobulin G (IgG) antibodies to the SFG rickettsiae. None of these sera were positive for IgG against typhus group rickettsiae. We detected Rickettsia africae–genotype DNA in 92.6% of adult Amblyomma variegatum ticks collected from domestic ruminants, but found no evidence of the pathogen in blood specimens from cattle, goats, or sheep. Sequencing of a subset of 21 rickettsia-positive ticks revealed R. africae variants in 95.2% (20/21) of ticks tested. Our findings show a high prevalence of R. africae variants in A. variegatum ticks in western Kenya, which may represent a low disease risk for humans. This may provide a possible explanation for the lack of African tick-bite fever cases among febrile patients in Kenya

Designing programs for eliminating canine rabies from islands: Bali, Indonesia as a case study

&lt;p&gt;Background: Canine rabies is one of the most important and feared zoonotic diseases in the world. In some regions rabies elimination is being successfully coordinated, whereas in others rabies is endemic and continues to spread to uninfected areas. As epidemics emerge, both accepted and contentious control methods are used, as questions remain over the most effective strategy to eliminate rabies. The Indonesian island of Bali was rabies-free until 2008 when an epidemic in domestic dogs began, resulting in the deaths of over 100 people. Here we analyze data from the epidemic and compare the effectiveness of control methods at eliminating rabies.&lt;/p&gt; &lt;p&gt;Methodology/Principal Findings: Using data from Bali, we estimated the basic reproductive number, R0, of rabies in dogs, to be ~1·2, almost identical to that obtained in ten–fold less dense dog populations and suggesting rabies will not be effectively controlled by reducing dog density. We then developed a model to compare options for mass dog vaccination. Comprehensive high coverage was the single most important factor for achieving elimination, with omission of even small areas (&#60;0.5% of the dog population) jeopardizing success. Parameterizing the model with data from the 2010 and 2011 vaccination campaigns, we show that a comprehensive high coverage campaign in 2012 would likely result in elimination, saving ~550 human lives and ~$15 million in prophylaxis costs over the next ten years.&lt;/p&gt; &lt;p&gt;Conclusions/Significance: The elimination of rabies from Bali will not be achieved through achievable reductions in dog density. To ensure elimination, concerted high coverage, repeated, mass dog vaccination campaigns are necessary and the cooperation of all regions of the island is critical. Momentum is building towards development of a strategy for the global elimination of canine rabies, and this study offers valuable new insights about the dynamics and control of this disease, with immediate practical relevance.&lt;/p&gt