Safety and immunogenicity of a new purified vero cell rabies vaccine (PVRV) administered by intramuscular and intradermal routes in healthy volunteers

Highlights

• A new purified vero-cell rabies vaccine (PVRV) was assessed in a phase I study.

• Preexposure prophylaxis with 3 doses was given in adults either intramuscularly or intradermally.

• The vaccine was found safe by both routes.

• The vaccine also showed good immunogenicity regardless of the route.

Abstract

Background

Rabies is 100% fatal but preventable with modern vaccines and immunoglobulins. There is a huge demand for rabies vaccines in developing countries of Asia and Africa. We have developed a new purified vero cell rabies vaccine (PVRV) and evaluated its safety and immunogenicity in healthy volunteers by intramuscular (IM) and intradermal (ID) routes of vaccination.

Methodology

Sixty adults aged between 18 and 50 years were recruited in this actively controlled Phase I clinical study and were randomized to receive three 1 ml or 0.1 ml doses of new PVRV intramuscularly or intradermally on days 0, 7 and 21. The control group received commercially available PVRV (Verorab) by intramuscular route. Adverse events (AEs) were recorded with diary cards till day 28 post-vaccination. Immunogenicity was assessed on day 0, 7, 21 and 42 by rapid fluorescence focus inhibition test (RFFIT).

Results

In all, 116 solicited local and systemic events were reported across the three groups. Most were mild and resolved without sequelae. Also the few unsolicited events, deemed unrelated to the study vaccines, caused no problems. No significant changes in the routine laboratory parameters were found. Two doses of a vaccine elicited protective titres (≥0.5 IU/ml) in all subjects, the GMTs varying between 0.57 and 0.69 IU/ml on day 7, 3.07 and 3.97 IU/ml on day 21, and 6.12 and 8.52 IU/ml on day 42 post-vaccination.

Conclusions

PVRV was well tolerated and showed good immunogenicity regardless of whether administered intramuscularly or, using a tenth of that volume, intradermally. Further studies with this new vaccine are warranted.

Introduction

Rabies is a fatal viral zoonotic disease that occurs at least in 100 countries and territories, mostly in the developing world. More than 3.3 billion people are living at risk of this severe infection [1], and estimated 55,000 deaths occur per year of which 20,000 in India alone and 24,000 in Africa (an incidence of 2 or 4/100,000 population at risk, respectively) [2]. Even these figures might be underestimates [3].

Limited access to vaccines is one of the reasons for this high mortality. As per an estimate, globally, ≥15 million people receive rabies prophylaxis annually [1], however, in India alone; there are >17 million animal bites annually, and the majority of the victims reside in the rural areas and are often unvaccinated [4].

High costs of the traditional rabies vaccines as well as availability pose a continuing problem in poor countries and no doubt contribute to the low coverage of vaccination. For years, safe and efficacious vaccines have been produced in cell cultures such as those derived from human diploid cell, purified vero cell, or chick embryo cells. All these vaccines have been used successfully in pre- and post-exposure prophylaxis [5]. Being very immunogenic, the cell culture vaccines (CCVs) can also be administered intradermally (ID) which is a major advantage, as the dose is only a fraction (0.1 ml) that used in the traditional intramuscular (IM) route, thereby reducing the cost of active immunization [3]. The ID administration is now routinely used even in the post-exposure prophylaxis in countries such as India, the Philippines, Sri Lanka and Thailand [6], [7].

Using the vero cell line, Serum Institute of India, Ltd. (SIIL), Pune, has developed its own rabies vaccine which is intended for both intramuscular and intradermal routes. After thorough single- and repeated-dose studies in rats and mice which had shown its good tolerability and non-teratogenicity, a Phase I clinical trial was considered justified. We here report the first results of this new vaccine in human volunteers.