Side-by-side Comparative Study of the Immunogenicity of the Intramuscular and Intradermal Rabies Post-exposure Prophylaxis Regimens in a Cohort of Suspected Rabies Virus Exposed Individuals.
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SUBMITTER: Auerswald H
PROVIDER: S-EPMC10506778 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
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Side-by-side Comparative Study of the Immunogenicity of the Intramuscular and Intradermal Rabies Post-exposure Prophylaxis Regimens in a Cohort of Suspected Rabies Virus Exposed Individuals.
Auerswald Heidi H Maestri Alvino A Touch Sothy S In Saraden S Ya Nisa N Heng Borita B Bosch-Castells Valérie V Augard Christele C Petit Céline C Dussart Philippe P Peng Yiksing Y Cantaert Tineke T Ly Sowath S
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20230901 6
All World Health Organization (WHO) pre-qualified rabies vaccines for humans are inactivated tissue culture rabies virus formulations produced for intramuscular (IM) administration. Due to costs and vaccine shortage, dose-saving intradermal (ID) administration of rabies post-exposure prophylaxis (PEP) is encouraged by WHO. This study compared the immunogenicity of the ID 2-site, 3-visit Institut Pasteur Cambodge (IPC) PEP regimen to the IM 1-site, 4-visit 4-dose Essen regimen using Verorab vacci ...[more]
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Project description:BackgroundThis phase III clinical trial compared the immunogenicity and safety of a purified chick-embryo cell rabies vaccine (PCECV) administered according to a shortened post-exposure prophylaxis (PEP) 4-site/1-week intradermal regimen, compared with the currently recommended 2-site/Thai Red Cross (TRC) regimen.Methodology/principal findingsThis controlled, open-label, multi-center study (NCT02177032) enrolled healthy individuals ≥1 year of age, randomized into 4 groups to receive intradermal PCECV according to one of the 2 regimens, with or without human rabies immunoglobulin (HRIG) administration at first visit (in adults only). Rabies virus neutralizing antibody (RVNA) concentrations and percentages of participants with RVNA concentrations ≥0.5 IU/mL (considered as adequate concentrations following PEP) were assessed up to day (D) 365 post-first vaccination. Non-inferiority of the 4-site/1-week regimen to the 2-site/TRC regimen was demonstrated if at D49, the lower limit of the 95% confidence interval (CI) for the difference between groups in the percentage of participants with adequate RVNA concentrations was >-5%. Of the 443 participants receiving the 4-site/1-week regimen, 88 adults received HRIG; 442 participants received the 2-site/TRC regimen (88 with HRIG). All participants achieved adequate RVNA concentrations by D14. At D49, the difference in percentage of participants with adequate RVNA concentrations between the 4-site/1-week and the 2-site/TRC groups was -1 (95%CI: -2.4-0.0); thus, non-inferiority was concluded. RVNA geometric mean concentrations were 18 IU/mL in 4-site/1-week groups and 12 IU/mL in 2-site/TRC groups at D14, and subsequently declined in all groups. RVNA concentrations were consistently lower in adults with HRIG administration than in those without. The 2 regimens had similar safety profiles. Of the 15 serious adverse events reported in 4-site/1-week groups and 19 in 2-site/TRC groups, none were vaccination-related.SignificanceThe data suggest that the 4-site/1-week regimen might be an alternative to current recommendations, with potential benefits in terms of improved cost-efficiency and compliance to vaccination.
| S-EPMC6005579 | biostudies-literature
Project description:BackgroundThe Strategic Advisory Group of Experts (SAGE) Working Group on rabies vaccines and immunoglobulins was established in 2016 to develop practical and feasible recommendations for prevention of human rabies. To support the SAGE agenda we developed models to compare the relative costs and potential benefits of rabies prevention strategies.MethodsWe examined Post-Exposure Prophylaxis (PEP) regimens, protocols for administration of Rabies Immunoglobulin (RIG) and inclusion of rabies Pre-Exposure Prophylaxis (PrEP) within the Expanded Programme on Immunization (EPI). For different PEP regimens, clinic throughputs and consumables for vaccine administration, we evaluated the cost per patient treated, costs to patients and potential to treat more patients given limited vaccine availability.ResultsWe found that intradermal (ID) vaccination reduces the volume of vaccine used in all settings, is less costly and has potential to mitigate vaccine shortages. Specifically, the abridged 1-week 2-site ID regimen was the most cost-effective PEP regimen, even in settings with low numbers of bite patients presenting to clinics. We found advantages of administering RIG to the wound(s) only, using considerably less product than when the remaining dose is injected intramuscularly distant to the wound(s). We found that PrEP as part of the EPI programme would be substantially more expensive than use of PEP and dog vaccination in prevention of human rabies.ConclusionsThese modeling insights inform WHO recommendations for use of human rabies vaccines and biologicals. Specifically, the 1-week 2-site ID regimen is recommended as it is less costly and treats many more patients when vaccine is in short supply. If available, RIG should be administered at the wound only. PrEP is highly unlikely to be an efficient use of resources and should therefore only be considered in extreme circumstances, where the incidence of rabies exposures is extremely high.
| S-EPMC7612382 | biostudies-literature
Project description:IntroductionThis phase I study explored the immunogenicity and reactogenicity of accelerated, Q7 fractional, intradermal vaccination regimens for COVID-19.MethodsParticipants (n = 60) aged 18-60 years, naïve to SARS-CoV-2 infection or vaccination, were randomly allocated into one of four homologous or heterologous accelerated two-dose, two-injection intradermal regimens seven days apart:(1) BNT162b2-BNT162b2(n= 20),(2) ChAdOx1- BNT162b2 (n = 20), (3) CoronaVac-ChAdOx1 (n = 10), and (4) ChAdOx1-ChAdOx1 (n = 10). CoronaVac and ChAdOx1 were 20%, and BNT162b2 17%, of their standard intramuscular doses (0.1 mL and 0.05 mL per injection, respectively). Humoral immune responses were measured through IgG response towards receptor binding domains (RBD-IgG) of ancestral SARS-CoV-2 spike protein and pseudovirus neutralization tests (PVNT50). Cellular immune responses were measured using ELISpot for ancestral protein pools.ResultsImmunogenicity was highest in regimen (2), followed by (1), (4), and (3) 2 weeks after the second dose (P < 0.001 for anti-RBD-IgG and P= 0.01 for PVNT50). Each group had significantly lower anti-RBD IgG (by factors of 5.4, 3.6, 11.6, and 2.0 for regimens (1) to (4), respectively) compared to their respective standard intramuscular regimens (P < 0.001 for each). Seroconversion rates for PVNT50 against the ancestral strain were 75%, 90%, 57% and 37% for regimens (1) to (4), respectively. All participants elicited ELISpot response to S-protein after vaccination. Adverse events were reportedly mild or moderate across cohorts.DiscussionWe concluded that accelerated, fractional, heterologous or homologous intradermal vaccination regimens of BNT162b2 and ChAdOx1 were well tolerated, provided rapid immune priming against SARS-CoV-2, and may prove useful for containing future outbreaks.
| S-EPMC9886662 | biostudies-literature
Project description:In developing countries, the cost of vaccination limits the use of prophylactic rabies vaccination, especially in cattle. Intradermal vaccination delivers antigen directly to an area with higher number of antigen-presenting cells. Therefore, it could produce equivalent or higher antibody titres than conventional intramuscular vaccination even when a lower dose is given. This study aimed to compare the antibody response in cattle vaccinated intramuscularly with 1mL of inactivated rabies vaccine (Raksharab, Indian Immunologicals) against intradermally vaccinated cattle with 0.2mL of the same vaccine. The study was conducted in Haa province of Bhutan where rabies is not endemic. One hundred cattle from 27 farms were selected for the study. Virus neutralising antibody (VNA) response was measured using the fluorescent antibody virus neutralisation test on the day of vaccination (day 0) and 14, 30, 60 and 90 days later. Overall, 71% of intradermally vaccinated cattle and 89% of the intramuscularly vaccinated cattle produced an adequate response (≥0.5IU/mL). On days 14 and 30 post vaccination fewer cattle (P<0.02) in the intradermal group had adequate titres with 36% and 58%, respectively, having titres ≥0.5 IU/mL compared to the equivalent figures of 78% and 77% in the intramuscular group. The mean VNA titres were lower for the intradermal group than intramuscular group (p<0.001) with the mean difference being > 0.6 IU/mL. Although low dose intradermal vaccination did produce a detectable antibody response, it was inferior to intramuscular vaccination. Thus, although intradermal vaccination has the potential to reduce the cost of vaccination by reducing the dose required, this study showed that a single dose of 0.2 mL intradermally was inferior to an intramuscular dose of 1 mL. Further research evaluating dose and dose regimen is needed before intradermal vaccination using the Raksharab rabies vaccine can be recommended in cattle.
| S-EPMC6557474 | biostudies-literature
Project description:BACKGROUND:Human rabies is a notifiable condition in Thailand, and 46 confirmed and probable cases were reported from 2010-2015; eleven were reported from Eastern Thailand. Although rabies is vaccine preventable, more than 90% of persons who died of rabies in Thailand either did not receive or inappropriately discontinued post-exposure prophylaxis (PEP). In 2012 Thailand launched a national animal rabies elimination program with the goal of elimination by 2020. One of the policies of this national program is to improve detection of animal rabies exposures, access to PEP, and adherence to vaccine schedules. To achieve this goal, several hospital-based electronic PEP surveillance systems have been instituted throughout Thailand. METHOD:Data from a voluntary, electronic hospital-based, rabies exposure and PEP surveillance system was analyzed from eight provinces in Eastern Thailand for the time period January 1 -December 31, 2015. The surveillance system collects data from all persons who present to an R36-integrated healthcare facility with a suspected rabies exposure, including characteristics of the biting animals, categorization of the rabies exposure, and adherence to PEP recommendations. The crude rate of healthcare seeking for a suspected rabies exposure was assessed by province, and a multivariable linear regression model was developed to determine the potential extent of undetected rabies exposures due to bite treatment at healthcare facilities that do not utilize the R36 system. Suspected rabies exposures were described by patient demographics, location of wound, and disposition of the offending animal. A comparison of adherence to intramuscular and intradermal vaccination regimens was performed and odds ratios were calculated for factors related to unadvised PEP discontinuation. RESULT:6,204 suspected rabies exposures were reported from eight Eastern Thailand provinces, yielding a crude exposure rate of 106 reported rabies exposures per 100,000 population. When adjusted for under-detection due to non-participating hospitals and province-level demographic differences, the estimated suspected rabies exposure rate was 204/100,000. Dogs were the main source of exposure (77.8%) and children age <15 years and elderly age >60 years had the highest overall reported exposure rate (189.7 and 189.2/100,000). Adherence to either the intramuscular 5-dose or the intradermal 4-dose PEP regimen was low (15.8% and 46.5%, respectively); rabies immunoglobulin was received by only 15% of persons for whom it was indicated. Persons with rabies exposures were more likely to discontinue the vaccination series against medical advice if they were male, aged 16-45, if they received immunoglobulin, or if received the intramuscular regimen. CONCLUSION:When adjusting for number of reporting hospitals, province population density, number of hospitals per population and average family income, the expected report rate increased 1.9-fold, indicating that there is likely a high level of under-detection of persons seeking medical care for suspected rabies exposures. Expanded implementation of electronic surveillance systems will likely improve reporting and the epidemiologic knowledge of rabies exposures. Analysis of data collected from this system revealed very low rates of adherence to rabies vaccination recommendations. PEP adherence was better by the intradermal route, which provides more support for its use in situations where it is economically feasible.
| S-EPMC7077841 | biostudies-literature
Project description:BackgroundFor immunocompromised patients (ICPs), administration of rabies immunoglobulins (RIG) after exposure is still recommended regardless of prior vaccination, due to a lack of data. We aimed to assess the 1-year boostability of a three-dose rabies pre-exposure prophylaxis (PrEP) schedule in individuals using immunosuppressive monotherapy.MethodsIn this prospective study, individuals on immunosuppressive monotherapy with a conventional immunomodulator (cIM) or a TNF-alpha inhibitor (TNFi) for a chronic inflammatory disease received a three-dose intramuscular PrEP schedule (days 0,7,21-28) with 1 mL Rabipur®, followed by a two-dose simulated post-exposure prophylaxis (PEP) schedule (days 0,3) after 12 months. Rabies neutralizing antibodies were assessed at baseline, on day 21-28 (before the third PrEP dose), day 60, month 12 and month 12 + 7 days. The primary outcome was 1-year boostability, defined as the proportion of patients with a neutralizing antibody titre of ≥ 0.5 IU/mL at month 12 + 7 days. Secondary outcomes were geometric mean titres (GMTs) and factors associated with the primary endpoint.ResultsWe included 56 individuals, of whom 52 completed the study. The 1-year boostability was 90% (47/52) with a GMT of 6.16 (95% CI 3.83-9.91). All participants seroconverted at some point in the study. Early response to PrEP (at day 21-28) was significantly associated with 100% boostability (Odds Ratio 51; 95% confidence interval [5.0-6956], P < 0.01). The vaccination schedule was safe and well tolerated. No vaccine-related serious adverse events occurred.ConclusionIn patients using immunosuppressive monotherapy, a three-dose rabies PrEP schedule followed by a two-dose PEP schedule is immunogenic, with all patients seroconverting at some point in the study. Although boostability 7 days after PEP was not 100%, nobody would wrongly be denied RIG when only administered to those who responded early to PrEP while reducing the administration of RIG by 73%.
| S-EPMC10075057 | biostudies-literature
Project description:BackgroundNew vaccines to prevent tuberculosis are urgently needed. MVA85A is a novel viral vector TB vaccine candidate designed to boost BCG-induced immunity when delivered intradermally. To date, intramuscular delivery has not been evaluated. Skin and muscle have distinct anatomical and immunological properties which could impact upon vaccine-mediated cellular immunity.MethodsWe conducted a randomised phase I trial comparing the safety and immunogenicity of 1×10(8)pfu MVA85A delivered intramuscularly or intradermally to 24 healthy BCG-vaccinated adults.ResultsIntramuscular and intradermal MVA85A were well tolerated. Intradermally-vaccinated subjects experienced significantly more local adverse events than intramuscularly-vaccinated subjects, with no difference in systemic adverse events. Both routes generated strong and sustained Ag85A-specific IFNγ T cell responses and induced multifunctional CD4+ T cells. The frequencies of CD4+ T cells expressing chemokine receptors CCR4, CCR6, CCR7 and CXCR3 induced by vaccination was similar between routes.ConclusionsIn this phase I trial the intramuscular delivery of MVA85A was well tolerated and induced strong, durable cellular immune responses in healthy BCG vaccinated adults, comparable to intradermal delivery. These findings are important for TB vaccine development and are of relevance to HIV, malaria, influenza and other intracellular pathogens for which T cell-inducing MVA-based vaccine platforms are being evaluated.
| S-EPMC5405058 | biostudies-literature
Project description:UnlabelledIt is accepted that an effective prophylactic HIV-1 vaccine is likely to have the greatest impact on viral transmission rates. As previous reports have implicated DNA-priming, protein boost regimens to be efficient activators of humoral responses, we sought to optimize this regimen to further augment vaccine immunogenicity. Here we evaluated single versus concurrent intradermal (i.d.) and intramuscular (i.m.) vaccinations as a DNA-priming strategy for their abilities to elicit humoral and cellular responses against a model HIV-1 vaccine antigen, CN54-gp140. To further augment vaccine-elicited T and B cell responses, we enhanced cellular transfection with electroporation and then boosted the DNA-primed responses with homologous protein delivered subcutaneously (s.c.), intranasally (i.n.), i.m., or transcutaneously (t.c.). In mice, the concurrent priming regimen resulted in significantly elevated gamma interferon T cell responses and high-avidity antigen-specific IgG B cell responses, a hallmark of B cell maturation. Protein boosting of the concurrent DNA strategy further enhanced IgG concentrations but had little impact on T cell reactivity. Interestingly protein boosting by the subcutaneous route increased antibody avidity to a greater extent than protein boosting by either the i.m., i.n., or t.c. route, suggesting that this route may be preferential for driving B cell maturation. Using an alternative and larger animal model, the rabbit, we found the concurrent DNA-priming strategy followed by s.c. protein boosting to again be capable of eliciting high-avidity humoral responses and to also be able to neutralize HIV-1 pseudoviruses from diverse clades (clades A, B, and C). Taken together, we show that concurrent multiple-route DNA vaccinations induce strong cellular immunity, in addition to potent and high-avidity humoral immune responses.ImportanceThe route of vaccination has profound effects on prevailing immune responses. Due to the insufficient immunogenicity and protection of current DNA delivery strategies, we evaluated concurrent DNA delivery via simultaneous administration of plasmid DNA by the i.m. and i.d. routes. The rationale behind this study was to provide clear evidence of the utility of concurrent vaccinations for an upcoming human clinical trial. Furthermore, this work will guide future preclinical studies by evaluating the use of model antigens and plasmids for prime-boost strategies. This paper will be of interest not only to virologists and vaccinologists working in the HIV field but also to researchers working in other viral vaccine settings and, critically, to the wider field of vaccine delivery.
| S-EPMC4054344 | biostudies-literature
Project description:ImportanceLow-dose intradermal influenza vaccines could be a suitable alternative to full intramuscular dose during vaccine shortages.ObjectiveTo compare the immunogenicity and safety of the influenza vaccine at reduced or full intradermal doses with full intramuscular doses to inform policy design in the event of vaccine shortages.Data sourcesMEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for studies published from 2010 until June 5, 2020.Study selectionAll comparative studies across all ages assessing the immunogenicity or safety of intradermal and intramuscular influenza vaccinations were included.Data extraction and synthesisData were extracted by a single reviewer and verified by a second reviewer. Discrepancies between reviewers were resolved through consensus. Random-effects meta-analysis was conducted.Main outcomes and measuresPrimary outcomes included geometric mean titer, seroconversion, seroprotection, and adverse events.ResultsA total of 30 relevant studies were included; 29 studies were randomized clinical trials with 13 759 total participants, and 1 study was a cohort study of 164 021 participants. There was no statistically significant difference in seroconversion rates between the 3-µg, 6-µg, 7.5-µg, and 9-µg intradermal vaccine doses and the 15-µg intramuscular vaccine dose for each of the H1N1, H3N2, and B strains, but rates were significantly higher with the 15-µg intradermal dose compared with the 15-µg intramuscular dose for the H1N1 strain (rate ratio [RR], 1.10; 95% CI, 1.01-1.20) and B strain (RR, 1.40; 95% CI, 1.13-1.73). Seroprotection rates for the 9-µg and 15-µg intradermal doses did not vary significantly compared with the 15-µg intramuscular dose for all the 3 strains, except for the 15-µg intradermal dose for the H1N1 strain, for which rates were significantly higher (RR, 1.05; 95% CI, 1.01-1.09). Local adverse events were significantly higher with intradermal doses than with the 15-µg intramuscular dose, particularly erythema (3-µg dose: RR, 9.62; 95% CI, 1.07-86.56; 6-µg dose: RR, 23.79; 95% CI, 14.42-39.23; 9-µg dose: RR, 4.56; 95% CI, 3.05-6.82; 15-µg dose: RR, 3.68; 95% CI, 3.19-4.25) and swelling (3-µg dose: RR, 20.16; 95% CI, 4.68-86.82; 9-µg dose: RR, 5.23; 95% CI, 3.58-7.62; 15-µg dose: RR, 3.47 ; 95% CI, 2.21-5.45). Fever and chills were significantly more common with the 9-µg intradermal dose than the 15-µg intramuscular dose (fever: RR, 1.36; 95% CI, 1.03-1.80; chills: RR, 1.24; 95% CI, 1.03-1.50) while all other systemic adverse events were not statistically significant for all other doses.Conclusions and relevanceThese findings suggest that reduced-dose intradermal influenza vaccination could be a reasonable alternative to standard dose intramuscular vaccination.
| S-EPMC7873776 | biostudies-literature
Project description:Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO-recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of ≥ 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857.
| S-EPMC4514298 | biostudies-literature