The key results are displayed in .
Summary of the results obtained for each participant.
Of the 12 participants the majority (75%) were women. Ages ranged from 20 to 71 years of age. All had received a total of 0.4
mL of previously available vaccines which is equivalent to 1
IU of rabies vaccine. Six of the 12 participants had received their previous rabies vaccine at a single clinic visit, five on two clinic visits, and one on four clinic visits. As shown in pre-booster antibody titres are consistent with the previous estimation two years earlier. All participants demonstrated postbooster antibody titres higher than the minimum considered consistent with immunity to rabies. The mean pre-booster titre was 0.18 (CI 0.12–0.25), and the mean postbooster titre was 17.33 (CI1.48–33.19). The mean antibody rise was 17.15
IU/mL. The range of antibody rises was very wide, varying from 1.75 to 69.93
IU/mL. The 95% confidence intervals are 1.326–32.973
The two results with increases in antibody titre of almost 70 skew the results and lie outside the 95% confidence intervals. Using a log transformation of the difference between pre- and posttitre levels gives a highly significant P value of <.01; the post-booster titre levels were significantly larger than the pre-booster titre levels (see ).
Scatter plot of antibody titre rise and age in years.
The most notable increases in antibody titre were observed in two women in their 30
s who had received their last rabies immunization between 4 and 5 years previously. Apart from age and gender no explanation for their high antibody response was determined. If these two results are excluded, the results did not show any obvious gender difference.
The apparent decline in antibody response with age is shown even if the two outliers are removed from the analysis as shown in .
Scatter plot of rise in tire after boosting with outliers removed against age.
suggests that there was a decline in antibody response after 10 years. The titre immediately prior to boosting did not appear to have any direct effect on the titre achieved after boosting immunization. This can be observed in .
Scatter plot of rise in antibody titre and year last immunized.
Scatter plot of pre-booster tire and fold rise in titre after boosting.
Participant 2 disclosed after the second blood sample that she had received chemotherapy for breast cancer since the previous study, if this had been disclosed earlier, she would have been excluded from the study. Interestingly, she demonstrated a good antibody response to the intradermal immunization. None of the participants reported any noticeable side effects from the immunization. None of the participants called the telephone helpline offered at entry to the study. Rabies remains a serious global challenge with an estimated 55,000 deaths each year [5
]. The availability of an effective vaccine is restricted by total vaccine production and relatively high cost. If intradermal rabies immunization schedules were introduced for pre-exposure prophylaxis, it would both increase the global supply of vaccine doses and reduce the cost per person immunised.
It is not possible to accurately determine the level of rabies virus neutralizing antibody adequate to provide protective immunity for humans. The World Health Organization regards 0.5
IU/mL as an adequate level of antibody after vaccination [2
] and that has been accepted by the authors of this paper, providing the basis for our confidence that 12 previously inadequately protected individuals now have adequate protective antibody levels. Previous work undertaken by the authors suggests that this protection should last for at least ten years [1
Versions of rabies vaccine previously used on the patients in this study contained 2.5
IU/mL. Many previous reports that discuss the effectiveness of both intramuscular and intradermal vaccines quote the dose administered in volume terms. The vaccine available for this study, Verorab, has twice the concentration containing 5
IU/mL, which is supplied in 0.5
mL vials each containing 2.5
IU of rabies vaccine. In order to avoid confusion this paper has quoted the dose in International Units rather than volume administered.
There were only 12 participants in this study so there is a possibility that they do not represent the true population of responders to boosting with intradermal vaccine. Calculation of the 95% confidence intervals of a small sample with a skewed distribution results, as in this case, in wide confidence intervals. Participants ranged widely in age and in time since previous rabies immunization. All developed an effective rabies antibody response. All 12 participants in this study demonstrated a good response to the booster doses supporting the hypothesis that antibody levels consistent with immunity to rabies are likely to be achieved if a total of 2
IU of rabies vaccine have been administered over three or more occasions. In this study the last dose had been administered within the previous 10 years. Taken with the findings of long-lasting immunity following intradermal rabies vaccine in our earlier study [1
], there is evidence to support a pre-exposure intradermal rabies immunization schedule based on delivering 2.0
IU spread over three doses. The interval between these three initial doses could be based on the observations of Thai studies which demonstrated effective protection with doses given on days 0, 7, and 28 described by Strady et al. [6
] who used the intramuscular route and Kamoltham et al. [7
] who used purified chick embryo cell vaccine given intradermally. A study by Naraporn et al. [8
] examined the immune response to rabies booster immunization after an interval of 5 years and showed that all 36 patients who completed the study at 28 days had a good anamnestic antibody response to two intradermal booster injections of purified duck embryo cell vaccine given 3 days apart. Malerczyk et al. [9
] report a study in 15 German veterinarians who had received purified chick cell embryo cell vaccine 14 years previously who were boosted with intramuscular purified chick cell embryo vaccine. All ten veterinarians who submitted blood samples after immunization demonstrated a good anamnestic response. Suwansrinon et al. [10
] describe a study in Thailand in which 53 patients who had received rabies immunization between 10 and 20 years previously were given two 0.9
IU doses of Vero cell rabies vaccine three days apart. Two weeks after immunization all had antibody levels that exceeded the critical threshold considered to provide adequate immunity of 0.5
The use of intradermal human diploid cell rabies vaccine for boosting purposes was examined in a study undertaken in 1987 which followed up 40 laboratory workers who had been given intradermal rabies vaccine in 3 separate doses totaling 0.75
]. Twenty of these workers demonstrated titres considered to be protective at 1 year, but by 2 years 5 were considered to have unprotective levels. Intradermal boosters given to 4 of these 5 laboratory workers produced high titres of rabies antibody. That study recommended serological testing every two years with a booster dose given to those with what are regarded as unprotective titre levels.
The observations of the study being reported in this report suggest that increasing the initial course to a total of 2
IU given over three clinic visits will provide effective rabies protection. Review of the literature and our previous study suggest that adequate immunity will be maintained for at least 10 years without the need for expensive serological testing or boosting. It is reasonable to conclude that immunization with at least 2
IU of rabies vaccine by the intradermal route should result in an antibody titre that will provide protection. This regimen could preserve the limited stocks of rabies biologicals, including rabies immunoglobulin. It is suggested that the time intervals used between doses can be based on the work of Strady et al. [6
], with an initial dose of 1
IU on day 0 followed by 0.5
IU on days 7 and 28. These doses are relatively easy to translate into volume terms based on the concentration of the vaccine available for use.
No adverse effects were reported after immunization supporting the hypothesis that boosters of two intradermal 0.5
IU Vero cell-derived rabies vaccine injections can safely be coadministered after 10 years with immunity maintained at an adequate level.
This study did not examine the effect of giving a single 0.5
IU dose of rabies vaccine as a 10-yearly booster; however the good level of response suggests that further cost and vaccine savings could be safely achieved. Further research to assess the increase in antibody titre following a single 0.5
IU dose of rabies vaccine is advisable. The absence of any serious side effects in this small sample of 12 patients given intradermal rabies vaccine is reassuring and helps to give confidence that the intradermal immunization route is not only effective but also safe [5