Booster effect of a new chromatographically purified Vero-cell rabies vaccine (CPRV): immunogenicity and safety of a single or double injection

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Booster effect of a new chromatographically purified Verocell rabies vaccine (CPRV): immunogenicity and safety of a single or double injection N. Picot’, V. LeMeneti, Y. Rotive13, C. Sch6nfeld4, J. C. Cetre’, F. Costyb, J. P. Grillet’, N. Lanta* and ‘Ecole Nationale Vete’rinaire de Toulouse, 23 J. La&* chemin des Capelles, 31076 Toulouse, France; ‘Aventis Pasteur, 2 avenue Pont Pasteur, 69367 Lyon, France; 3Centre National de REfbrence Rage, Institut Pasteur, 28 rue Dr Roux, 75724 Park, France; 41nstitutfir Tropenmedizin Engeldamm 62-64, 10179 Berlin, Germany; ‘Ecole Nationale Vett%naire de Lyon, 1 ave Bourgelat - BP 83, 69280 Marcy L’Etoile, France; 61nstitut Pasteur de Bruxelles, rue Engeland 642, B-l 180 Bruxelles, Belgium; 7Mutualitt+ Sociale Agricole, 2 place du Mar&ha1 Leclerc, 02008 Laon Cedex, France; 8Ecole Nationale Vedrinaire de Nantes, Chantrerk, Route Gachet, 44087 Nantes Cedex 3, France Keywords: rabies, Vero-cell vaccine, chromatographically purified vaccine, booster schedules, immune response, safety, Europe Rabies, a lethal viral infection transmitted by mammals, is responsible for the death of more than 40 000 people each year (WHO, 1996). Recommendations for post-exposure vaccination vary from between 2 and 5 injections, with or without babies immunoglobulins (RIG), according to the patient’s rabies vaccination status and the severity of the rabies-prone wound. A 2dose schedule administered 3 days apart without RIG, as soon as possible after exposure, ;s recommended by the WHO 119921 and ACIP (1991) for nreviouslv vaccinated p‘atienti. Unlike HD& (dumai~diploid-cell vaccine) which has been associated with a few safety concerns, PVRV (purified Vero-cell rabies vaccine) has

AND HYGIENE

been well tolerated. This latter has been further purified to produce a new chromatographically purified rabies vaccine (CPRV; Aventis Pasteur, Lyon, France). The safety and the immunogenicity ofprimary immunization with CPRV have been compared and validated versus the et PVRV and HDCV (LANG et al., 1998; SABCHAREON al., 1999). The anamnestic effect of CPRV administered intramuscularly and according to either a pre-exposure booster regimen at 1 year (1 dose; study 1) or a simulated post-exposure booster regimen (2 doses; study 2) was tested (Table 1). After appropriate local and national ethics committee review, 2 trials were performed in 1997 in Europe (France, Belgium, Germany) among young veterinary students, staff and travellers vaccinated at least 1 year after a previous anti-rabies immunization. The studies were performed according to the latest revision of the Declaration of Helsinki (Hong Kong, 1989), Good Clinical Practice (GCP) as well as local and US regulatory requirements. Written informed consent was obtained from all volunteers prior to study inclusion. Safety results were satisfactory, with reports of less than 15% of solicited, non-severe systemic reactions, with no anaphylaxis nor severe delayed-hypersensitivity reaction, such as has been described in 6% of HDCV booster recipients (Table 2). Each of the 508 subjects included in the immunogenicity analyses increased considerablv their baseline antibodv level following booster injection(s), and all achieved “neutralizing aiti-rabies antibody levels [detected by rapid fluorescent focus et al., 1973)] over the WHO inhibition test (SMITH 0.5 IU/mL acceptable level for seroprotection (Figure). The quality ofthe anamnestic response was attested to by the 1O-fold rise of neutralizing anti-rabies antibody titres between pre- and post-booster titres (lo- 14 days after booster) .‘The typebf cell-culture vaccine used (PVRV or HDCV) for nrevious mimarv immunization had no effect on the magnitude of the booster response to CPRV, indicating the potential for interchangeability of CPRV with the established cell-culture vaccines. The number of booster doses of CPRV (1 or 2) likewise had no impact on the anamnestic response, attesting to the high immunogenicity of a single booster dose of CPRV in pre-immunized subjects. Only the baseline titre of rabies neutralizing antibodies before booster seemed to be predictive of the intensity of the antibody response. The titre increase was inversely proportional to the I

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Table 1. Characteristics of healthy adults receiving CPRV booster dose(s) according to internationally and post-exposure regimens Characteristic Number enrolled Age (years) Mean f- SD Range Female [n (%)] Number of booster dose Vaccination schedule completed Withdrawal before the last visit Subjects lost to follow-up Subjects evaluable for immunogenicity Subjects evaluable for safety analysis

(2001) 95,342-344

A

1 (study 1) or 2 (study 2) approved pre-exposure

Study 1

Study 2

338

179

37.2 f 15 20.6-76.0 155 (45.9%) 1 338

25.7 f 7 19.6-57.6 111 (62.0%) 2 176 4 2”

;

analysis

I

DO

D14

DO

D3

DIO

338 338

335 336

179 179

176 178

173 175

“Subjects who completed the trial but did not return their self-monitoring form at the end of the study despite several attempts to contact them. CPRV, chromatographically purified Vero-cell rabies vaccine; D, day.

*Author for correspondence.

NEW BABIES

VACCINE

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Table 2. Number and percentage of subjects experiencing and each type of reaction following 1 (study 1) or 2 booster CPRV in previously immunized healthy adults

Study 2

Study 1

Kz

Dose 2’

Dose lb

Total” At least 1 systemic reaction Headache Nausea Myalgia Arthralgia Fever Asthenia Lymphadenopathy Urticaria Pain Diarrhoea Rigors Dizziness Malaise Vomiting

at least 1 reaction (study 2) dose(s) of

;;

12 6 3 1

y;

1 1 3 1 1 -

-

:, 1 -

(0:6) -

Values given are numbers of individuals in each category (percentage of the study population in parentheses). Study population was “336, b178, ’ 175 individuals analysed. CPRV, chromatographically purified Vero-cell rabies vaccine.

I

1 I

150

Study 1 RFFIT

3 3 100 d 9o E-2 788

0

60 $1 20 10 0

Time in days (D)

Titre < 0.5 Titre [0.5IUimL 2.5 IUlmL]

Titre > 2.5 IUimL

Study 2 RFFIT

b

DO

D3

Dlo

Time in days (D) Figure. Kinetics of anti-rabies antibody titres following 1 (study 1) or 2 booster (study 2) dose(s) of CPRV in previously immunized adults in Europe, analysed by sub-group according to baseline antibody levels: CO.5 IU/mL, 10.5-2.5 IU/mL] and 32.5 IU/mL. CPRV, chromatographically purified Vero-cell rabies vaccine; RFFIT, rapid fluorescent focus inhibition test; GMT, geometric mean antibody titre; GMR, geometric mean ratio. The bars represent 95% confidence intervals.

baseline antibody level, i.e., the lower the pre-booster titre, the higher the post-to-pre titre ratio. These data support the safety and immunogenicity of CPRV in preand post-exposure booster strategies of primed healthy subjects with reliable vaccination history, demonstrate the interchangeability of this new-generation vaccine, and warrant further studies evaluating the value of a single booster in the case of exposure, which might be sufficient in this kind of population.

One or 2 booster doses of CPRV were safe and well tolerated among 517 previously immunized healthy adults with reliable vaccination. The 2 booster regimens produced significant and comparable anamnestic responses that were more pronounced in the subjects with low baseline rabies neutralizing antibody levels. CPRV produced an adequate anamnestic response in subjects previously immunized with either PVRV or HDCV, and was not associated with hypersensitivity reactions. Our

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N. PICOT ETAL.

data suggest, based on the humoral response to vaccination, that although 2 doses are recommended, a single booster dose may be sufficient in healthy immunocompetent vaccinees adequately primed by PVRV or HDCV, and substantiate the safe and efficient utilization CPRV in a booster regimen of 1 or 2 single doses.

of

References ACIP, Advisory Committee on Immunization Practices. (1991). Rabies prevention: United States, 1991. Morbidity and Monaliy Weekly Reports, 40, 1- 19. Lang, J., Cetre, J. C., Picot, N., Lanta, M., Briantais, P., Vital, S., Le Mener, V., Lutsch, C. & Rotivel, Y. (1998). Immunogenicity and safety in adults of a new chromatographically purified Vero-cell rabies vaccine (CPRV): a randomized double-blind trial with purified Vero-cell rabies vaccine (PVRV). Biologicals, 26, 299-308.

Sabchareon, A., Lang, J., Attanath, P., Sirivichayakul, S., Le Mener, V., Pengsaa, K., Prarinyanuphab, V., PojjaroenAnant, C., Nimnual, S., Riffard, P. & Chanthavanich, P. (1999). A new Vero cell rabies vaccine: results of a comparative trial with HDCV in children. Clinical Infectious Diseases, 29, 141-149. Smith, J. S., Yager, P. A. & Baer, G. M. (1973). A rapid tissue culture test for determining rabies neutralizine antibodies. WHO Monograph Series, 23,-354-357. WHO (1992). WHO Expert Committee on Rabies. Eighth Report. Geneva, Switzerland: World Health Organization, WHO Technical Report Series, no. 824. WHO (1996). Fighting Disease: Fostering Development. Geneva, Switzerland: World Health Organization. Received 18 February 2000; revised 3 October 2000; accepted for publication 3 October 2000

British Contributions to Medical Research and Education in Africa after the Second World War f5.00 plus p&p Enormous advances have been made in twentieth century medicine, but the work of following those advances is complex. This new Witness Seminar transcript from the Welcome Trust’s History of Twentieth Century Medicine Group publishes discussion among medical scientists, clinicians and historians, who considered postwar efforts to improve health services, and research in non-infectious diseases, nutrition, vector-borne diseases and helminth eradication.

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