Safety and Immune Response of a Rabies Vaccine With the Essen Schedule and a Two-Dose Booster

Immunogenicity and Safety of Freeze-Dried Human Rabies Vaccine (Vero Cell) With the "Essen" Immunization Schedule and a Two-Dose Booster in Chinese Healthy Subjects Aged 10-60 Years: A Randomized, Blinded, and Comparable Vaccine-Controlled Non-Inferiority Phase III Clinical Trial.

Rabies is caused by rabies virus with a 100% mortality rate in humans. Most of cases occur in Africa and Asia, mainly in underserved populations. Rabies is a vaccine-preventable disease in both humans and animals. Over the years, the Vero cell rabies vaccine has been recognized by the World Health Organization (WHO) and the European Union, and is widely used globally. Currently, one of the post-exposure prophylaxis (PEP) regimens recommended by the World Health Organization (WHO) is the five-dose "Essen" regimen (1-1-1-1-1), involving one intramuscular dose administered on days 0, 3, 7, 14, and 28 respectively. This clinical trial was to assess the immunogenicity and safety of a freeze-dried human rabies vaccine (Vero Cell) in healthy population for the large-scale developing, and explore the booster vaccination.

Rabies is caused by rabies virus with a case fatality rate approaching 100% in humans. Studies reported that about 59000 human deaths and over 3.7 million disability-adjusted life years lost every year. Most of cases occur in Africa and Asia, mainly in underserved populations, with approximately 40% of cases in children aged <15 years. Fortunately, rabies is a vaccine-preventable disease in both humans and animals. Post-exposure prophylaxis (PEP), is the critical intervention for preventing the onset of the disease.

Conventional Vero cell rabies vaccines have been used globally for decades, demonstrating excellent safety and immunogenicity. However, their production typically requires the use of animal-derived components, such as fetal bovine serum or human serum albumin, in the cell culture medium. This practice raises potential concerns regarding the risk of contamination with adventitious agents, batch-to-batch variability, and the potential for allergic reactions. To address these limitations, a new generation of purified Vero rabies vaccine produced in serum-free medium has been developed. This vaccine uses the same Pitman-Moore virus strain as the traditional vaccines but is manufactured without any human or animal serum-derived components, significantly reducing the risk of extraneous protein contamination and representing a substantial advancement in vaccine technology and safety. The shift to a serum-free production process, while a clear advantage for safety, raises critical questions regarding the vaccine's immunogenicity and the duration of protection it confers.

This study aims to systematically evaluate the available evidence of the serum-free Vero cell rabies vaccine. First, we will critically assess its immunogenicity in PEP settings. Second, we will assess the long-term persistence of protective antibody titers following primary vaccination. Finally, we will discuss the rationale for and evidence on booster vaccination strategies.

Inclusion Criteria:

• Healthy subjects aged 10-60 years as established by medical history and clinical examination
• The subjects are able to understand and sign the informed consent
• Female subjects aged 18-60 years must have a negative urine pregnancy test result and commit to using contraception for 2 months following the first vaccine dose in this study.
• Subjects who can and will comply with the requirements of the protocol
• Subjects with temperature ≤37.0°C on axillary setting

Exclusion Criteria:

Exclusion Criteria for the first dose:

• Subject who was administered human rabies vaccine or rabies immunoglobulin.
• Subject that has a medical history of any of the following: allergic history, or allergic to any ingredient of vaccine, especially allergic to neomycin.
• Has been diagnosed or suspected of having an immune deficiency, autoimmune disease, or immune system disorder.
• History of thyroidectomy, or thyroid disease requiring treatmentin the past 12 months
• Bleeding disorder diagnosed by a doctor or significant bruising or bleeding difficulties with injections or blood draws
• History of epilepsy, convulsions or convulsions, or a family history of psychosis.
• Absence of spleen, functional absence of spleen, and any circumstances leading to absence of spleen or splenectomy.
• Have a malignant tumor in active phase, or a tumor that have been treated but not clearly cured, or may relapse during the study period.
• In the past 6 months, there have been immunosuppressive therapy, cytotoxic therapy, inhaled corticosteroids (excluding corticosteroid spray therapy for allergic rhinitis, and surface corticosteroid therapy for acute non-complicated dermatitis).
• Taking anti-TB or HIV treatment.
• Any prior administration of immunoglobulin or blood products in last 3 months.
• Coagulopathy (such as coagulation factor deficiency, coagulative disorders, platelet abnormalities) or obvious bruising or coagulation impairment
• Any prior administration of other research drugs in last 30 days
• Any prior administration of attenuated live vaccine in last 4 weeks
• Any prior administration of subunit or inactivated vaccines in last 2 weeks
• Have acute diseases, severe chronic diseases, acute exacerbation of chronic diseases, or those with fever
• Suspected or have a history of injury caused by warm-blooded mammals in last 3 months.
• Women who are breastfeeding, pregnant, or planning to become pregnant in 2 months past the first dose.
• Use of antipyretic, analgesic, or antiallergic drugs within 3 days
• Having used other investigational or unregistered products (drugs or vaccines) within 6 months prior to the vaccination of the study vaccine, or having plans to participate in other clinical studies after enrollment in this clinical study (except for emergency-use novel coronavirus vaccines, but the vaccination details must be recorded in the concomitant medication section)
• Planning to move out of the local area or be away from the local area for a long time before the end of the study;
• Any condition that in the opinion of the investigator, may interfere with the evaluation of study objectives

Exclusion Criteria for other doses:

• Any incidences in the first dose exclusion criteria occur after inclusion
• Grade 3 or higher systemic adverse reactions related to this study, or intolerable injection site adverse reactions, that occurred between the previous vaccination and the current vaccination.
• Any serious adverse events caused by vaccination.
• Other reactions that in the opinion of the investigator ( include: severely serious symptom of pain, swelling, Limitation of motion, continuous high fever, headache and other Systemic or local reactions )