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Clinical Trial
. 2025 May 27;19(5):e0013118.
doi: 10.1371/journal.pntd.0013118. eCollection 2025 May.

Long-term persistence and boostability of immune responses following different rabies pre-exposure prophylaxis priming schedules of a purified chick embryo cell rabies vaccine administered alone or concomitantly with a Japanese encephalitis vaccine

Tomas Jelinek  1 , Mirjam Schunk  2 , Emil C Reisinger  3 , Marylyn M Addo  4 , Ursula Wiedermann  5 , Marco Costantini  6 , Maria Lattanzi  6 , Michele Pellegrini  6 , Ilaria Galgani  6 ; Rabies-018 V49_23E1 study group
Affiliations
Clinical Trial

Long-term persistence and boostability of immune responses following different rabies pre-exposure prophylaxis priming schedules of a purified chick embryo cell rabies vaccine administered alone or concomitantly with a Japanese encephalitis vaccine

Tomas Jelinek et al. PLoS Negl Trop Dis. .

Abstract

Background: Rabies pre-exposure prophylaxis (PrEP) is recommended to individuals at risk for exposure to rabies. Three intramuscular doses of the purified chick embryo cell (PCEC) rabies vaccine can be administered according to a conventional (four-week) or an accelerated (one-week) regimen.

Methodology/principal findings: This phase III, open-label study (NCT02545517) was an extension of the NCT01662440 study where immune responses of different primary PrEP regimens with PCEC rabies vaccine and Japanese encephalitis (JE) vaccine were assessed. Adults who had completed the parent study and received three doses of rabies PrEP regimens, concomitantly with a JE vaccine or alone (i.e., Rabies+JE-Accelerated, Rabies+JE-Conventional, and Rabies-Conventional groups) were enrolled in this extension study. Here we evaluated the long-term (up to 10 years after completing the primary vaccination) immunogenicity and boostability of PCEC rabies vaccine, and the safety of booster dose(s). Immunogenicity was assessed in terms of rabies virus neutralizing antibody (RVNA) concentrations, and titers ≥0.5 international units (IU)/mL were considered adequate for protection. Participants with RVNA concentrations <0.5 IU/mL were eligible for receiving PCEC rabies vaccine booster(s). Of the 459 participants enrolled in this study, 77.6% completed the trial. At the study end, the probability of detecting adequate RVNA concentrations in unboosted participants was 57.8%, 60.2%, and 62.0% for the Rabies+JE-Accelerated, Rabies+JE-Conventional, and Rabies-Conventional groups, respectively. Overall, 68.6% of all participants had RVNA concentrations ≥0.5 IU/mL at any timepoint and did not require a booster dose during the study follow-up period. Of the 144 participants with RVNA concentrations <0.5 IU/mL at any timepoint, 132 needed one booster dose throughout the follow-up period (Years 3-10) and 12 needed multiple booster administrations. No safety concerns were identified.

Conclusion/significance: The PCEC rabies vaccine administered alone/concomitantly with the JE vaccine provides adequate immunity for up to 62% of unboosted participants at study end.

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Conflict of interest statement

I have read the journal's policy and the authors of this manuscript have the following competing interests: Marco Costantini, Maria Lattanzi, Michele Pellegrini, and Ilaria Galgani are GSK employees and hold financial equities in GSK. Tomas Jelinek received support from GSK for the present manuscript. He has also received grants or contracts, consulting fees, payment or honoraria, and support for attending meetings and/or travel from Abbott Laboratories, Astellas Pharma, Astra Zeneca, Bavarian Nordic, BioNTech, Boehringer Ingelheim, Clover Biopharmaceuticals, Janssen Vaccines (formerly Crucell), Dr. Falk Pharma GmbH, Emergent BioSolutions, GSK, Glenmark Pharmaceuticals, Hermes Arzneimittel, Serum Institute of India, Janssen, Medicago, Moderna, Novartis Vaccines, Pfizer, R-Biopharm AG, Sanofi Pasteur, Merck Sharp & Dohme, Sekisui Virotech GmbH, Takeda Pharmaceuticals, Themis Bioscience, and Valneva. He also received payments for expert testimonies from Bavarian Nordic, BioNTech, GSK, Moderna, Pfizer, and Takeda Pharmaceuticals, and participated in data and safety monitoring board or advisory boards within Bavarian Nordic, Emergent BioSolutions, GSK, Moderna, Pfizer, Sanofi Pasteur, Merck Sharp & Dohme, Takeda Pharmaceuticals, and Valneva. He also received equipment, materials, drugs, or medical writing assistance from Astra Zeneca, Bavarian Nordic, BioNTech, GSK, Glenmark Pharmaceuticals, Hermes Arzneimittel, Moderna, Pfizer, Sanofi Pasteur, Merck Sharp & Dohme, Takeda Pharmaceuticals, and Valneva. Mirjam Schunk declares that her institution received funding from GSK for the conduct of the clinical trial. She was part of the data and safety monitoring board during the conduct of the clinical trial. Emil C. Reisinger declares that his institution received funding from GSK for conducting the clinical trial. He also received travel support for attending a meeting from GSK (Impfexperten Meeting) without any personal or institutional payment. Ursula Wiedermann declares that her institution has received a grant from GSK (§98 research third party grant) for the conduct of the clinical trial. Marylyn M. Addo has nothing to declare.

Figures

Fig 1
Fig 1. Plain language summary.
Fig 2
Fig 2. Study design and participant flowchart.
*Twelve participants who received a PCEC rabies vaccine booster dose after the completion of the parent study [12] and before entering this extension study were included in the post-booster immunogenicity analysis. For these participants, the rabies virus neutralizing antibody concentrations were not tested before the administration of the booster dose. FAS-2 includes all participants who provided immunogenicity data and PPS-2 includes all participants in FAS-2 who had no major protocol deviations leading to exclusion. FAS-1 includes all participants who received at least one booster dose during the trial and provided immunogenicity data and PPS-1 includes all participants in the FAS-1 who had no major protocol deviations leading to exclusion. Rabies+JE-Accelerated, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the accelerated one-week schedule; Rabies+JE-Conventional, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the conventional four-week schedule; Rabies-Conventional, participants who received rabies vaccine alone according to the conventional four-week schedule; Y, year; IU, international units; PCEC, purified chick embryo cell; N, number of participants; FAS, full analysis set; PPS, per-protocol set.
Fig 3
Fig 3. Kaplan-Meier estimation of the survival function of RVNAs (full analysis set 2).
RVNA, rabies virus neutralizing antibody; IU, international units; Rabies+JE-Accelerated, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the accelerated one-week schedule; Rabies+JE-Conventional, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the conventional four-week schedule; Rabies-Conventional, participants who received rabies vaccine alone according to the conventional four-week schedule.
Fig 4
Fig 4. Adjusted hazard ratio for time to first RVNA concentration below 0.5 IU/mL (full analysis set 2).
RVNA, rabies virus neutralizing antibody; IU, international units; Rabies+JE-Accelerated, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the accelerated one-week schedule; Rabies+JE-Conventional, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the conventional four-week schedule; Rabies-Conventional, participants who received rabies vaccine alone according to the conventional four-week schedule; NA, not applicable; 95% CI, 95% confidence interval.
Fig 5
Fig 5. Probability of long-term RVNA persistence (full analysis set 2).
RVNA, rabies virus neutralizing antibody; IU, international units; Rabies+JE-Accelerated, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the accelerated one-week schedule; Rabies+JE-Conventional, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the conventional four-week schedule; Rabies-Conventional, participants who received rabies vaccine alone according to the conventional four-week schedule; D, day; Y, year. Note: Error bars represent 95% confidence intervals.
Fig 6
Fig 6. Overall (Y3–Y10) boostability of the PCEC rabies vaccine (full analysis set 1).
Y, year; PCEC, purified chick embryo cell; RVNA, rabies virus neutralizing antibody; IU, international units; GMC, geometric mean concentration; GMR, geometric mean ratio; Rabies+JE-Accelerated, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the accelerated one-week schedule; Rabies+JE-Conventional, participants who received rabies vaccine concomitantly with Japanese encephalitis vaccine according to the conventional four-week schedule; Rabies-Conventional, participants who received rabies vaccine alone according to the conventional four-week schedule. Note: Error bars represent 95% confidence intervals.
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References

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