Scaling-up the delivery of dog vaccination campaigns against rabies in Tanzania

An increasing number of countries are committing to meet the global target to eliminate human deaths from dog-mediated rabies by 2030. Mass dog vaccination is central to this strategy. To interrupt rabies transmission from dogs to humans, the World Health Organization recommends that vaccination campaigns should be carried out every year in all dog-owning communities vaccinating 70% of their susceptible dogs. Monitoring and evaluation of dog vaccination campaigns are needed to measure progress towards elimination. In this study, we measured the delivery performance of large-scale vaccination campaigns implemented in 25 districts in south-east Tanzania from 2010 until 2017. We used regression modelling to infer the factors associated with, and potentially influencing the successful delivery of vaccination campaigns. During 2010–2017, five rounds of vaccination campaigns were carried out, vaccinating in total 349,513 dogs in 2,066 administrative vaccination units (rural villages or urban wards). Progressively more dogs were vaccinated over the successive campaigns. The campaigns did not reach all vaccination units each year, with only 16–28% of districts achieving 100% campaign completeness (where all units were vaccinated). During 2013–2017 when vaccination coverage was monitored, approximately 20% of vaccination units achieved the recommended 70% coverage, with average coverage around 50%. Campaigns were also not completed at annual intervals, with the longest interval between campaigns being 27 months. Our analysis revealed that districts with higher budgets generally achieved higher completeness, with a twofold difference in district budget increasing the odds of a vaccination unit being reached by a campaign by slightly more than twofold (OR: 2.29; 95% CI: 1.69–3.09). However, higher budgets did not necessarily result in higher coverage within vaccination units that were reached. We recommend national programs regularly monitor and evaluate the performance of their vaccination campaigns, so as to identify factors hindering their effective delivery and to guide remedial action.     

Think globally,act locally: the role of local demographics and vaccination coverage in the dynamic response of measles infection to control

The global reduction of the burden of morbidity and mortality owing to measles has been a major triumph of public health. However, the continued persistence of measles infection probably not only reflects local variation in progress towards vaccination target goals, but may also reflect local variation in dynamic processes of transmission, susceptible replenishment through births and stochastic local extinction. Dynamic models predict that vaccination should increase the mean age of infection and increase inter-annual variability in incidence. Through a comparative approach, we assess national-level patterns in the mean age of infection and measles persistence. We find that while the classic predictions do hold in general, the impact of vaccination on the age distribution of cases and stochastic fadeout are mediated by local birth rate. Thus, broad-scale vaccine coverage goals are unlikely to have the same impact on the interruption of measles transmission in all demographic settings. Indeed, these results suggest that the achievement of further measles reduction or elimination goals is likely to require programmatic and vaccine coverage goals that are tailored to local demographic conditions.     

Oral vaccination in the control of feral rabies

The authors briefly report the results of laboratory and epidemiological investigations on living modified and inactivated antirabies vaccines, started in 1975 and carried out in collaboration with public health authorities and scientific institutions. The antirabies oral vaccination of foxes, using a live and modified vaccine (SADB19 Tüb.) began in Brescia province (Val Camonica) in 1984 and was extended in 1985 to Bolzano and Trento provinces. Since July 1986 no more cases of rabies have been observed in Italy. The problems related to the distribution in the territory of live and modified antirabies vaccines, the immunological value of inactivated vaccines, the connections between sylvatic rabies and bat rabies (or pseudorabies), are discussed.     

Population monitoring in support of a rabies vaccination program for skunks in Arizona

Three population monitoring methods were evaluated in support of a trap/vaccinate/release program for controlling a bat variant of rabies virus in skunks (Mephitis mephitis) in Flagstaff, Arizona (USA). Skunks were the primary species targeted for population monitoring during the program, but feral cats were also monitored as they represented an abundant secondary vector species capable of rabies transmission. Skunks were vaccinated and released, except for a subset tested for rabies. All captured cats were placed in the local animal shelter. Spotlight surveys essentially did not detect skunks, and were not able to detect reductions in the cat population. Catch-per-unit-effort marginally tracked population trends, but a passive track index adapted for an urban setting was most sensitive for detecting changes in skunk and cat populations. Mark-recapture population estimates could not be validly calculated from the data on captures and recaptures due to multiple violations of analytical assumptions.     

Metapopulation dynamics of rabies and the efficacy of vaccination

Spatial structure in a host population results in heterogeneity in transmission dynamics. We used a Bayesian framework to evaluate competing metapopulation models of rabies transmission among domestic dog populations in villages in Tanzania. A proximate indicator of disease, medical records of animal-bite injuries, is used to infer the occurrence (presence/absence) of suspected rabid dog cases in one month intervals. State-space models were used to explore the implications of different levels of reporting probability on model parameter estimates. We find evidence for a relatively high rate of infection of these populations from neighbouring districts or from other species distributed throughout the study area, rather than from adjacent wildlife protected areas, suggesting wildlife is unlikely to be implicated in the long-term persistence of rabies. Stochastic simulation of our highest ranked models in vaccinated and hypothetical unvaccinated populations indicated that pulsed vaccination campaigns occurring from 2002 to 2007 reduced rabies occurrence by 57.3 per cent in vaccinated villages in the 1 year following each pulse, and that a similar regional campaign would deliver an 80.9 per cent reduction in occurrence. This work demonstrates how a relatively coarse, proximate sentinel of rabies infection is useful for making inferences about spatial disease dynamics and the efficacy of control measures.     

Effect of the contents and form of rabies glycoprotein on the potency of rabies vaccination in cattle

One of the methods used for controlling cattle rabies in Brazil consists of vaccination. Sometimes, however, rabies occurs in cattle supposedly protected. Since rabies vaccine batches are officially controlled by tests performed on laboratory animals, it is questionable whether the minimal mandatory requirements really correspond to immunogenicity in the target species. We have analyzed the association among potencies of rabies vaccines tested by the NIH test, the contents and form (free-soluble or virus-attached) of rabies glycoprotein (G) in the vaccine batches, and the virus-neutralizing antibodies (VNA) titers elicited in cattle. No correlation was found between G contents in the vaccine batches and the NIH values, whatever the presentation of G. There was no correlation either between NIH values and VNA titers elicited in cattle. There was, however, a positive correlation (r = 0.8681; p = 0.0001) between the amounts of virion-attached G present in the vaccine batches and VNA elicited in cattle. This was not observed when the same analysis was performed with total-glycoprotein or free-soluble glycoprotein. The study demonstrated that NIH values can not predict the effect of the immunogen in cattle. On the other hand, the quantification of virus-attached rabies glycoprotein has a strong correlation with VNA elicited in cattle.     

Prevention of rabies virus infection in dogs by a recombinant canine adenovirus type-2 encoding the rabies virus glycoprotein

Safe and effective vaccination is important for rabies prevention in animals. Although several genetically engineered rabies vaccines have been developed, few have been licensed for use, principally due to biosafety concerns or due to poor efficacy in animal models. In this paper, we describe the construction and characterization of a replication-competent recombinant canine adenovirus type-2 expressing the rabies virus glycoprotein (SRV9 strain) by a different strategy from that reported previously, i.e., the recombinant genome carrying the glycoprotein cDNA was generated by a series of strictly gene cloning steps, infectious recombinant virus was obtained by transfecting the recombinant genome into a canine kidney cell line, MDCK. This recombinant virus, CAV-E3delta-CGS, was subcutaneously injected into dogs. All vaccinated dogs produced effective neutralizing antibodies after one inoculation and a stronger anamnestic immune response was produced after booster injection. The immunized dogs could survive the challenge of 60,000 mouse LD50 CVS-24, which is lethal to all unimmunized dogs and is comparable to the conventional vaccines. The immunity lasts for months with a protective level of neutralizing antibody. This recombinant virus would be an alternative to the attenuated and the inactivated rabies vaccines and be prospective in immunizing dogs against rabies.     

Genetic control of serum neutralizing-antibody response to rabies vaccination and survival after a rabies challenge infection in mice.

Quantitative differences in serum neutralizing-antibody (SNAb) responses to rabies vaccination and survival after a rabies challenge infection between two inbred mice strains, C3H/J and C57BL/6J, were shown to be under genetic control. A 99% confidence limit calculated from the SNAb response titers of 14 C57BL/6J mice resulted in an upper limit for the SNAb response titer of C57BL/6J mice at 50.63. A SNAb titer less than or equal to 50.63 in response to rabies vaccination was assigned the phenotype of hyporesponder, and a SNAb titer greater than 50.63 in response to rabies vaccination was assigned the phenotype of hyperresponder in this study. The hyper-SNAb response to rabies vaccination and the higher frequency of survival after rabies challenge infection behave as Mendelian dominant alleles in F1 hybrids (C3H/J X C57BL/6J) and backcross (BC) (F1 [C3H/J X C57BL/6J] X C57BL/6J) progeny. Both a relatively hyper-SNAb response and a higher frequency of vaccine-inducible survival phenotypes occur in C3H/J mice. On the other hand, both the relatively hypo-SNAb response and a lower frequency of vaccine-inducible survival phenotypes behave as Mendelian recessive alleles and occur in C57BL/6J mice. C3H/J mice are H-2 Kk, and C57BL/6J mice are H-2 Kb. All three phenotypic traits (H-2 type, SNAb response, and survival after rabies challenge infection) segregate as independent (unlinked) monogenic traits in BC progeny (F1 [C3H/J X C57BL/6J] X C57BL/6J). The genetically controlled survival trait is inducible by rabies vaccination, but SNAb response is not a parameter that measures successful vaccine induction of preexposure protection from a rabies challenge infection in the BC progeny. The essential role of vaccination in developing preexposure protection in genetically responsive mice is confirmed, but indicates that in vitro measurements other than SNAb titers need to be developed to identify mice that have failed to achieve preexposure protection by rabies vaccination. This study confirms Lodmell's findings (D. L. Lodmell and B. Chesebro, J. Virol. 50:359-362, 1984; D. L. Lodmell, J. Exp. Med. 157:451-460, 1983) that susceptibility to rabies infection is genetically controlled in some mice strains. Additionally, this study indicates that conventional rabies vaccination even with more potent vaccines may not induce protection from infection in some genetically susceptible individuals.     

A descriptive epidemiological study of raccoon rabies in a rural environment

A recent outbreak of rabies in raccoons, Procyon lotor (L.), in Loudoun County, Virginia (1981-82), prompted a study of the epidemiology of the disease. Parameters studied included the occurrence and movement of the disease over time, sex and age relationships, and behavior patterns of raccoons. During the 18 mo, 427 raccoons were tested, of which 75% were infected with rabies virus. Interpretation of rainfall data and the subsequent spatial occurrence of infected raccoons within the county indicated a cause and effect relationship. The submission rate of female raccoons was greater than that of males. The female raccoons (adult and juvenile) were also found to be infected with the virus more often than the males. Behavior of infected raccoons in a rural environment was similar to those observed in the southeastern United States during earlier epizootics of rabies. The presence of a skunky odor on infected raccoons may be a characteristic of raccoon rabies.     

Immunisation coverage in Lusaka, Zambia; implications of the social setting.

This paper develops a conceptual framework for examining the process of immunisation and explores the sociodemographic determinants of vaccination in Zambia. About 300 mothers with children under 3 years of age were interviewed in urban Lusaka. The analyses suggest that sociostructural, as well as cultural, processes influence the attrition process and immunisation programmes should focus on the uniqueness of each stage. In addition, programmes to improve women's education and to reduce male gender preferences are needed.     

Risk factors for pre-treatment mortality among HIV-infected children in rural Zambia: a cohort study

Background

Many HIV-infected children in sub-Saharan Africa enter care at a late stage of disease. As preparation of the child and family for antiretroviral therapy (ART) can take several clinic visits, some children die prior to ART initiation. This study was undertaken to determine mortality rates and clinical predictors of mortality during the period prior to ART initiation.

Methods

A prospective cohort study of HIV-infected treatment-naïve children was conducted between September 2007 and September 2010 at the HIV clinic at Macha Hospital in rural Southern Province, Zambia. HIV-infected children younger than 16 years of age who were treatment-naïve at study enrollment were eligible for analysis. Mortality rates prior to ART initiation were calculated and risk factors for mortality were evaluated.

Results

351 children were included in the study, of whom 210 (59.8%) were eligible for ART at study enrollment. Among children ineligible for ART at enrollment, 6 children died (mortality rate: 0.33; 95% CI:0.15, 0.74). Among children eligible at enrollment, 21 children died before initiation of ART and their mortality rate (2.73 per 100 person-years; 95% CI:1.78, 4.18) was significantly higher than among children ineligible for ART (incidence rate ratio: 8.20; 95% CI:3.20, 24.83). In both groups, mortality was highest in the first three months of follow-up. Factors associated with mortality included younger age, anemia and lower weight-for-age z-score at study enrollment.

Conclusions

These results underscore the need to increase efforts to identify HIV-infected children at an earlier age and stage of disease progression so they can enroll in HIV care and treatment programs prior to becoming eligible for ART and these deaths can be prevented.     

Domestic dog origin of canine distemper virus in free-ranging wolves in Portugal as revealed by hemagglutinin gene characterization

Serologic evidence for canine distemper virus (CDV) has been described in grey wolves but, to our knowledge, virus strains circulating in wolves have not been characterized genetically. The emergence of CDV in several non-dog hosts has been associated with amino acid substitutions at sites 530 and 549 of the hemagglutinin (H) protein. We sequenced the H gene of wild-type canine distemper virus obtained from two free-ranging Iberian wolves (Canis lupus signatus) and from one domestic dog (Canis familiaris). More differences were found between the two wolf sequences than between one of the wolves (wolf 75) and the dog. The latter two had a very high nucleotide similarity resulting in identical H gene amino acid sequences. Possible explanations include geographic and especially temporal proximity of the CDV obtained from wolf 75 and the domestic dog, taken in 2007-2008, as opposed to that from wolf 3 taken more distantly in 1998. Analysis of the deduced amino acids of the viral hemagglutinin revealed a glycine (G) and a tyrosine (Y) at amino acid positions 530 and 549, respectively, of the partial signaling lymphocytic activation molecule (SLAM)-receptor binding region which is typically found in viral strains obtained from domestic dogs. This suggests that the CDV found in these wolves resulted from transmission events from local domestic dogs rather than from wildlife species.     

Intracerebral vaccination suppresses the spread of rabies virus in the mouse brain

To investigate the efficacy of intracerebral (IC) immunization in preventing viral spread in the brain, we immunized mice with inactivated rabies virus via the subcutaneous (SC) or IC route, followed by administration of a lethal dose of rabies virus (challenge virus standard strain), directly into the brains of immunized mice. Progressive paralytic neurological signs were observed in control and 75% of SC immunized mice, whereas only 20% of IC immunized mice exhibited symptoms. Neutralizing antibody titers in blood plasma were significantly elevated in SC and IC immunized mice, with the highest levels seen in IC immunized mice. Analysis of whole brain lysates revealed a strong induction of immunoglobulin in the brains of IC immunized mice that had virus neutralizing activity. Histopathological examination of brain tissue revealed mild encephalitis and disseminated viral antigen in control and SC immunized mice, but rare in IC immunized mice. These results suggest that IC immunization induces a preventive humoral immune response against intracerebrally inoculated rabies virus. Induction of neutralizing antibody in cerebrospinal fluid represents a putative therapeutic measure for the treatment of rabid animals and humans.