Immunogenicity Study of Abbreviated Rabies Preexposure Vaccination Schedules

Authors

  • Pakamatz Khawplod PhD,

    1. Queen Saovabha Memorial Institute of the Thai Red Cross Society and the Department of Medicine, King Chulalongkorn University Hospital, Bangkok, Thailand
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  • Henry Wilde MD,

    Corresponding author
    1. Queen Saovabha Memorial Institute of the Thai Red Cross Society and the Department of Medicine, King Chulalongkorn University Hospital, Bangkok, Thailand
      Henry Wilde, MD, Queen Saovabha Memorial Institute of the Thai Red Cross Society and the Department of Medicine, King Chulalongkorn University Hospital, 1871 Rama IV Road, Bangkok 10330, Thailand. E-mail: wildehenry@yahoo.com
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  • Maneerat Benjavongkulchai MSc,

    1. Queen Saovabha Memorial Institute of the Thai Red Cross Society and the Department of Medicine, King Chulalongkorn University Hospital, Bangkok, Thailand
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  • Chakrapol Sriaroon MD,

    1. Queen Saovabha Memorial Institute of the Thai Red Cross Society and the Department of Medicine, King Chulalongkorn University Hospital, Bangkok, Thailand
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  • Pranee Chomchey NP

    1. Queen Saovabha Memorial Institute of the Thai Red Cross Society and the Department of Medicine, King Chulalongkorn University Hospital, Bangkok, Thailand
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Henry Wilde, MD, Queen Saovabha Memorial Institute of the Thai Red Cross Society and the Department of Medicine, King Chulalongkorn University Hospital, 1871 Rama IV Road, Bangkok 10330, Thailand. E-mail: wildehenry@yahoo.com

Abstract

Objective To evaluate abbreviated preexposure rabies vaccination schedules that would reduce cost and shorten time required for completion.

Method A random prospective immunogenicity study, using a group of 96 volunteer preclinical veterinary students, primary school children, and hospital-based health care workers. They were divided into six groups and administered abbreviated schedules of preexposure tissue culture rabies vaccines. Neutralizing antibodies were determined on days 0 and 360, and following boosters on days 367 and 374.

Results All subjects, including one group that received only 0.1 mL intradermally at two sites on one day, had detectable neutralizing antibody titers 1 year later and responded with an accelerated antibody response when given booster injections.

Conclusion It might be possible to develop a 1-week and even one clinic visit preexposure vaccine schedule that would provide at least 1 year of immune memory.

Travelers who are likely to have exposures to dogs or cats in canine rabies–endemic countries are being advised to complete a preexposure rabies vaccine series (PREP) prior to departure.1 This has assumed greater importance due to severe shortages or unavailability of human or equine rabies immunoglobulins in most of the regions where the risk is highest.2 The World Health Organization (WHO) recommends preexposure vaccine schedules consisting of one intramuscular (IM) full dose or one 0.1 mL intradermal (ID) dose of any WHO-recognized tissue or avian culture rabies vaccine injected on days 0, 7, 21, or 28.1 These schedules have been shown to result in an excellent and long-lasting immune response.1 Tourists, business travelers, diplomats, emergency assistance workers, or military personnel may not have enough time to complete the series of three injections before leaving. They may receive one injection and are told to complete the series at their destination. This may not be possible or is neglected. It is difficult to assess the actual risk of rabies exposure, which does not only depend on the length of stay in an endemic region. Phanuphak3 reported an incidence of 13 animal bites per 1,000 travelers in an average of 17 days touring Thailand. Steffen4 found 1.7 animal bites per 1,000 month in a general survey of travelers. Most tourist destinations in Asia and Africa are in high-risk canine rabies–endemic countries where there may be total lack or short supply of quality vaccines and rabies immunoglobulins. Prompt postexposure prophylaxis (PEP) is then uncertain or even impossible and can be accomplished only after costly medical evacuation and dangerous delay.5 The risk of children being severely bitten by dogs is estimated to be two to four times greater than for adults.2,6. Bites in small children are often on hands, trunk, or face and almost half of worldwide rabies deaths are in children.6,7 There have been recommendations to include rabies vaccination as a routine public health measure in children living in the worst canine rabies–endemic regions. However, a cost-effectiveness study, comparing universal preexposure vaccination of children with postexposure prophylaxis without immunoglobulin, showed that this is not cost–benefit effective with current preexposure vaccination schedules and the present cost of quality vaccines.8 Many, if not most, travelers remain abroad for much less than 1 year. These considerations have led us to carry out a prospective study using abbreviated preexposure (PREP) schedules.

Materials and methods

We recruited 96 volunteers aged 8 to 40, with a male to female ratio of 41:45. None were at an occupationally increased risk of rabies exposure during the study year. They were randomized into six groups and given abbreviated vaccine schedules using WHO-recognized purified Vero cell rabies vaccine (Aventis-Pasteur Co., Lyon, France) or purified chick embryo cell rabies vaccine (Chiron Co., Ankleshuan, India). Our schedules were selected to determine whether one could achieve immune memory lasting at least 1 year that would result in a satisfactory accelerated neutralizing antibody response when boosters are administered in a simulated rabies exposure 360 days later. All volunteers (or parents) were informed of the purpose of this study and signed a consent form. They were instructed to obtain booster injections in the event of any later rabies exposure and contact one of the investigators if such an exposure occurred during the study period; before we have the antibody profiles from days 360 and 374. Neutralizing rabies antibodies were determined at the immunology laboratory of this institute using the rabies fluorescent focus inhibition test as previously described.9 Exclusion criteria were prior rabies vaccination and any immunosuppressive illness or medication. This study was approved by the ethics committee of the Thai Red Cross Society.

Results

There were no reports of adverse side effects on aggressive questioning other than minor itching and erythema at injection sites. All subjects (A–F) had no detectable neutralizing antibody titers on day 0. When tested on day 360, those who had received PREP (groups A–D) and were tested, had detectable neutralizing antibody titers. Groups E and F had received PEP starting on day 0 and had detectable titers on day 360 before receiving the two booster injections. Of those tested, all responded with an accelerated immune response on day 367 (Table 1). Groups E and F were recruited from among WHO category II rabies-exposed regular clinic patients.

Table 1.  Postexposure schedules A–F
 Day
0360367374
  1. ID = intradermal vaccination; IM = intramuscular; PVRV = purified Vero cell rabies vaccine; GMT = geometric mean titer; PEP = postexposure prophylaxis.

Group A—Primary series: 0.1 mL injected ID at two sites on days 0, 7, and 28
 Boosters: 0.1 mL ID on days 360 and 363 (vaccine used PVRV batch 0525, potency 7.5 IU/0.5 mL)
 GMT<0.030.9629.1449.39
 Range 0.32–2.956.73–227.7613.05–308.44
 >0.5 IU/mL 13/1616/1616/16
 Male/female5/11 
 Age (years)18–35 
Group B—Primary series: 0.1 mL injected ID at two sites on days 0, 3, and 7
 Boosters: 0.1 mL ID on days 360 and 363 (vaccine used PVRV batch 0525, potency 7.5 IU/0.5 mL)
 GMT<0.031.1222.99105.08
 Range 0.30–4.765.91–295.3726.11–496.74
 >0.5 IU/mL 15/1616/1616/16
 Male/female4/12 
 Age (years)18–32 
Group C—Primary series: 1.0 mL IM at one site on days 0, 3, and 7
 Boosters: 0.1 mL ID on days 360 and 363 (vaccine used PVRV batch 0525, potency 7.5 IU/0.5 mL)
 GMT<0.030.9735.16125.00
 Range 0.27–4.7611.97–191.5229.73–800.00
 >0.5 IU/mL 16/2017/1720/20
 Male/female8/12 
 Ages (years)18–40 
Group D—Primary series: 0.1 mL ID at two sites (same day)
Boosters: 0.1 mL ID on days 360 and 363 (vaccine used PVRV, batch 0525, potency 7.5 IU/0.5 mL)
 Day0360367374
 GMT<0.030.419.1551.96
 Range 0.06–3.673.36–22.6313.63–141.42
 >0.5 IU/mL 5/1310/109/9
 Male/female7/7 
 Age (years)8–11 
Group E—Patients who received PEP with Thai Red Cross ID schedule (0.1 mL ID at two sites on days 0, 3, and 7 and one site  on days 28 and 90; vaccine used PVRV batch 0525, potency 7.5 IU/0.5 mL)
 Day071428
 GMT<0.030.065.565.84
 Range 0.03–0.151.15–53.821.77–20.73
 >0.5 IU/mL 0/1010/1010/10
 Male/female5/5 
 Age (years)21–30 
Group F: Patients who received PEP with Thai Red Cross ID schedule (0.1 mL ID at two sites on days 0, 3, and 7 and one site  on days 28 and 90; vaccine purified chick embryo, Chiron, batch 2190011, potency 7.0 IU/mL)
 Day071428
 GMT<0.030.068.545.96
 Range <0.03–0.311.56–27.260.96–18.22
 >0.5 IU/mL 0/2019/1920/20
 Male/female12/8 
 Age (years)17–23 

Discussion and conclusions

Even 0.1 mL of a WHO-accepted tissue culture rabies vaccine injected at two ID sites (both deltoid regions) conferred immune memory for at least 1 year. Two booster injections 1 year later resulted in an accelerated immune response indicating that immunoglobulin may not be necessary if such a subject experiences a rabies exposure within 1 year. A simultaneously performed independent study used one full IM dose of rabies vaccine and followed 20 volunteers for 6 months [P. Suandork and colleagues (Department of Pediatrics, King Chulalongkorn University Hospital), personal communication, unpublished]. All his subjects had detectable or higher antibody titers at 6 months but were not followed longer. Suandork’s and our preliminary studies need to be repeated with larger statistically significant numbers of subjects and for longer than 1 year.

Acknowledgments

We are grateful for the enthusiastic efforts from our nursing staff, volunteer veterinary students, and hospital nurses. We are also indebted to Professors Visith Sitprija and Narongsak Chaiyabutr for their support of this study.

Declaration of interests

This study received financial support from Aventis-Pasteur Co. and the Thai Red Cross Society. H. W. is a recipient of an ongoing research grant from the Thai National Center for Genetic Engineering and Biotechnology. All other authors have no conflicts of interest to declare.

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