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

Abstract

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.

Keywords: immunogenicity; maternally-acquired immunity; mortality; nonspecific effects of vaccines; sex.

Figure 1

Flowchart of study subjects. SW = sterile water (control); RV = rabies vaccine.

Figure 2

Rabies virus neutralizing antibody titers (RVNA) in the treatment and control groups at 6 weeks of age (prevaccination), 21 days after first injection at 9 weeks of age (rabies vaccine in the treatment group and sterile water in the control group), and 21 days after second injection at 13 weeks of age (rabies vaccine in both groups). The dashed horizontal line shows the threshold of seroprotection (0.5 IU/mL). The numbers above each group show the number of subjects (n) and the number and percentage (%) seroresponding (RVNA titers ≥0.5 IU/mL).

Figure 3

Survival curve of study subjects (n = 358) by group and sex, from 6 weeks to 13 weeks of age (time 0 = day of 1st injection). SW = sterile water (control); RV = rabies vaccine.