Factors influencing the immune response after a double-dose 2-visit pre-exposure rabies intradermal vaccination schedule: A retrospective study
Introduction
Rabies is a neglected but preventable tropical disease with a case-fatality rate of nearly 100% [1]. The global annual death toll is approximately 59 000 cases. Asia and Africa have greater prevalence rates than the other continents. In these regions, 40% of cases occur in children aged <15 years [2,3]. In travellers the death rate is much lower [4]. Pre-exposure prophylaxis (PrEP) using rabies vaccine is an important part of rabies prevention but only exceptionally used in endemic setting [5]. However, even when administered long before exposure, PrEP simplifies the post-exposure prophylaxis (PEP) because immunoglobulins are not needed anymore and only 2 vaccinations are needed instead of 4 [3]. The new 2018 World Health Organization (WHO) guideline recommends PrEP with rabies vaccine for individuals at high risk for exposure to rabies due to their occupation, travel, and/or residence in an endemic setting with limited access to timely and adequate PEP [6]. For both PEP and PrEP, vaccines can be administered by either the intradermal (ID) or the intramuscular (IM) route [6]. The current WHO-recommended PrEP schedules are the double-dose ID vaccine or the 1 site IM vaccine administered on days 0 and 7 [6].
Belgian military personnel are required to receive rabies PrEP before deployment since 2009. There is one routine schedule currently in use in the Belgian Armed Forces: the double-dose 2-visit intradermal (a double dose of 0.1 mL [2 × 0.1ID] injected into the inner surface of the forearms on days 0 and 7) rabies vaccination schedule (22ID), followed by a serological control by rapid fluorescent focus inhibition test (RFFIT) between day 14 and day 35. The WHO specified a minimum serum antibody concentration of 0.5 IU/mL [6] to be used as a measure of adequate immune response after PrEP. An alternative schedule, exceptionally used in Belgian military personnel, is the single-dose 3-visit intradermal (one dose of 0.1 mL [0.1ID] on days 0, 7, and 28) rabies vaccination schedule (31ID) without any subsequent serological control. Our team recently showed in a randomized clinical trial that, in healthy adults, the 22ID schedule was safe and not inferior to the 31ID schedule, and outweighed it in terms of proportion of participants with long-lasting protection defined as RFFIT levels >10 IU/mL (96% vs 83%) following the booster injection [7]. Despite the new WHO guideline, these 22ID PrEP regimens are only used in some countries (like Belgium, Denmark, or The Netherlands) and the countries that are still reticent argue a lack of data about pediatric and elderly patients, female subjects or the necessity to test antibodies after finishing PrEP [8].
The aim of the present study is to evaluate, in real setting, the 22ID rabies vaccination schedule in the Belgian Armed Forces and to determine whether timescale changes in the schedule and variability in serology timing have an influence on the neutralizing antibody response.
Section snippets
Study design
This is a single-center retrospective study based on electronic health record vaccination data from the Center for Infectious Diseases, Queen Astrid Military Hospital (Brussels – Belgium).
Population
We screened for inclusion members of the Belgian Armed Forces who were vaccinated with the 22ID regimen between 1 January 2017 and 31 December 2018. Subjects who started vaccination prior to 2017, who received an incomplete vaccination schedule, who have been vaccinated with another regimen (like 31ID, IM,
Results
Out of the 2028 subjects who received a rabies vaccination between 1 January 2017 and 31 December 2018, 301 met eligibility criteria and have been included (Fig. 1). Subjects who didn't complete the 22ID schedule or didn't performed the RFFIT within this timeframe were excluded. This occurred mainly because individuals forgot their second visit or were deployed on mission.
Of the 301 subjects included, 276 (91.7%) were male and the age at baseline ranged from 19 to 61 years, with a median (IQR)
Discussion
Seroconversion rate in this retrospective cohort (98,7%) confirms that 22ID rabies PrEP vaccination schedules are highly effective and can elicit an adequate immune response in almost all subjects. The 4 subjects (1.3%) who did not have an adequate antibody titer (RVNA < 0.5 IU/mL) were all young (<40 year), male subjects, and 3 had the “correct” while 1 had the “late” vaccination schedule. Notably, 3 of the 4 non-responders had noted aberrant timings of serology testing after their double dose
Author contributions
Benjamin Damanet: Conceptualization, Methodology, Data Curation, Formal Analysis, Writing- Original draft preparation, Visualization. Diana Isabela Costescu Strachinaru: Conceptualization, Methodology, Ethics Committee, Writing- Original draft preparation. Patrick Soentjens: Methodology, Project Administration, Writing- Reviewing and Editing, Supervision, Validation.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
The authors declare that they have no competing interests.
Acknowledgments
We thank the Data Management Team of the Military Hospital Queen Astrid, especially Patrick Calonne, for granting access to the database pertaining to rabies vaccination.
References (24)
- et al.
Human rabies: neuropathogenesis, diagnosis, and management
Lancet Neurol
(2013) Weekly epidemiological record. Rabies vaccines: WHO position paper - april 2018
World Heal Organ - Tech Rep Ser
(2018)- et al.
Immunogenicity of a modified intradermal pre-exposure rabies vaccination schedule using a purified chick embryo cell vaccine: an observational study
Trav Med Infect Dis
(2013) - et al.
Rabies antibody response after two intradermal pre-exposure prophylaxis immunizations: an observational cohort study
Trav Med Infect Dis
(2018) Sexual dimorphism of humoral immunity with human vaccines
Vaccine
(2008)- et al.
Pre-exposure rabies vaccination using purified chick embryo cell rabies vaccine intradermally is immunogenic and safe
J Pediatr
(2007) - et al.
Is the rabies virus neutralizing antibody titer stable during long-term storage?
Trav Med Infect Dis
(2019) - et al.
Correction to: estimating the global burden of endemic canine rabies (PLoS negl trop dis, 9, 5)
PLoS Neglected Trop Dis
(2015) - et al.
Animal-associated exposure to rabies virus among travelers, 1997–2012
Emerg Infect Dis
(2015) - et al.
Protecting children from rabies with education and pre-exposure prophylaxis: a school-based campaign in El Nido, Palawan, Philippines
PLoS One
(2018)
Preexposure intradermal rabies vaccination: a noninferiority trial in healthy adults on shortening the vaccination schedule from 28 to 7 days
Clin Infect Dis
Cited by (2)
Factors influencing the immune response after a single-dose 3-visit pre-exposure rabies intradermal vaccination schedule: A retrospective multivariate analysis
2020, Travel Medicine and Infectious DiseaseCitation Excerpt :Gender- and age-related differences in seroconversion rates, GMTs and RVNA persistence after different ID PrEP (31ID and 22ID) and PEP rabies schedules have also been reported by other teams [16–19], but it is still debatable if these findings have a clinical impact. Moreover, other studies did not find such differences [20,21]. In our study, females were found to have significantly higher chances of eliciting RVNA ≥3 IU/mL than males (p = 0.005) when adjusting for other predictors.
One-week, two-visit, double-dose, intra-dermal (2<sup>2</sup>ID) rabies vaccination schedule for travelers: Time/dose sparing, effective but “off label”
2020, Travel Medicine and Infectious Disease
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These authors contributed equally to this work.