Seroconversion following incomplete human rabies postexposure prophylaxis

Vaccine 28 (2010) 6523–6526 Contents lists available at ScienceDirect Vaccine journal homepage: www.elsevier.com/locate/vaccine Seroconversion following incomplete human rabies postexposure prophylaxis夽 Kis Robertson a,∗ , Sergio Recuenco b , Michael Niezgoda b , Enid J. Garcia c , Charles E. Rupprecht b a Epidemic Intelligence Service, Office of Workforce and Career Development, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30333, United States Poxvirus and Rabies Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention (CDC), 1600 Clifton Rd NE, Atlanta, GA 30333, United States c Office of Epidemiology, Puerto Rico Department of Health, United States b a r t i c l e i n f o Article history: Received 16 April 2010 Accepted 29 June 2010 Available online 14 July 2010 Keywords: Rabies Immunogenicity Seroconversion a b s t r a c t In August 2008, CDC and the Puerto Rico Department of Health conducted a serosurvey of patients who had discontinued rabies postexposure prophylaxis (PEP) prior to completing a schedule of five vaccine doses. The objective was to determine whether further vaccination of these patients was needed based on serum rabies neutralizing antibody levels. Eighteen patients consented to serology using the rapid fluorescent focus inhibition test. The World Health Organization’s cutoff value of 0.5 IU/mL was used as the basis for recommending PEP continuance, while complete virus neutralization at the 1:5 dilution indicated seroconversion per current Advisory Committee for Immunization Practices recommendations. Serum samples were collected a median of 147 days (range 24–215) after receipt of the last vaccine dose. Ten patients were recommended for PEP continuance for titers below 0.5 IU/mL; however, of 11 patients, 33% of 2-dose, 100% of 3-dose, and 100% of 4-dose patients exhibited seroconversion. These findings corroborate previous studies that suggest a less than five-dose rabies vaccine regimen elicits adequate immunogenicity against rabies. © 2010 Published by Elsevier Ltd. 1. Introduction The most lethal of the infectious diseases, rabies is caused by neuroinvasive viruses in the Lyssavirus genus. Transmission typically occurs through bites from infected mammals. A rapidly progressive encephalomyelitis usually develops after a 1–3 month incubation period. Offsetting the fact that rabies is essentially incurable once symptoms begin is its almost universal preventability through the use of timely and properly administered postexposure prophylaxis (PEP). In previously non-immunized persons, rabies PEP as endorsed by the 2008 Advisory Committee on Immunization Practices (ACIP) includes the administration of rabies immune globulin (RIG) on day 0 and a 5-dose 1-mL series of cell-culture rabies vaccine given intramuscularly on days 0, 3, 7, 14, and 28 [1] in what is colloquially referred to as the Essen schedule. In 1975, the World Health Organization (WHO) first recommended this schedule for PEP (with an optional sixth dose at day 90) using the then-newly available human diploid cell vaccine (HDCV) [2]. This course represented a significant departure from what was utilized at that time, 夽 Disclaimer: The findings and conclusions in this report are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention. ∗ Corresponding author. Tel.: +1 404 639 1067; fax: +1 404 639 1564. E-mail address: kir6@cdc.gov (K. Robertson). 0264-410X/$ – see front matter © 2010 Published by Elsevier Ltd. doi:10.1016/j.vaccine.2010.06.102 as previous to 1980, the only non-nervous tissue culture vaccine commercially available in the United States was the duck embryo vaccine, a low potency biologic which required a daily series of 14–23 doses [3]. In 1997, a second cell-culture rabies vaccine – the purified chick embryo vaccine (PCECV) – gained FDA-licensure, and its recommended administration mirrored the schedule already in place for HDCV [4]. In June 2009, the ACIP voted to change the recommended number of vaccine doses used for PEP to four by dropping the fifth-dose scheduled for day 28 [5]. This decision was based on a review of published and unpublished data assembled by a multi-institutional working group that was established to reassess the 2008 ACIP recommendations [6]. The oldest and most compelling study presented in this review includes a serostudy of 45 patients in Iran who had been bitten by confirmed rabid animals and were found to have, 16 days after receiving the fourth dose of HDCV, neutralizing antibody titers exceeding the accepted thresholds of seroconversion set by both the ACIP and WHO [7]. Later, two separate investigations of recipients of rabies PEP consisting of PCECV and RIG found that patients had achieved adequate antibody levels by day 18 [8,9]. Along with immunogenicity data, further support of a reduced vaccine schedule has been inferred from the absence of human rabies cases in the United States among rabies PEP recipients failing to receive a full 5-dose vaccine course. During mid-2007 to early 2009, human rabies vaccine was available only on a limited basis in the United States and Puerto Rico. Temporary suspension of HDCV production resulted in a subopti- 6524 K. Robertson et al. / Vaccine 28 (2010) 6523–6526 mal supply of FDA-licensed rabies vaccines. To conserve the supply and prevent the development of a vaccine shortage, widespread restrictions were enacted for the use of these biologics. Access to rabies vaccine was granted to physicians and other healthcare providers only after consultation with state/local public health officials. Vaccine use for pre-exposure immunization was restricted to first responder groups at highest risk of occupational exposures, such as rabies diagnosticians and animal control workers. Both healthcare and public health practitioners were strongly encouraged by the CDC to base prophylaxis decisions on ACIP guidelines as a means of limiting the number of individuals receiving unnecessary PEP. Concerns about the vaccine supply peaked in the summer of 2008, when PEP demand outpaced existing stores of HDCV and threatened continued availability of PCECV [10]. In August 2008, the Puerto Rico Department of Health (PRDH) requested assistance from the CDC after the department encountered difficulties in procuring vaccine doses sufficient to initiate and complete PEP for individuals who had recently been bitten by animals. In Puerto Rico, procurement, storage, and delivery of rabies PEP to medical facilities is arranged by the PRDH. Inquiry by the CDC revealed that largely as a consequence of recent organizational changes within the PRDH that placed unforeseen burdens on a limited staff, resolution of rabies virus exposure risk assessments and follow-up for animal bite patients had been less than ideal during the preceding 12-month period. The CDC assisted the PRDH in evaluating patients for exposure and identifying those in need of rabies PEP. Human RIG and rabies vaccine had been administered to a number of patients previous to being evaluated by the CDC; however, due to loss to follow-up, it was not initially known by PRDH whether these patients had completed the 5-dose series. For patients who had self-discontinued PEP prior to receiving five vaccine doses, serological analysis, in addition to patient evaluation, was pursued to determine the need to recommend administration of additional vaccine to these patients. In this report, findings of the conducted serostudy are described. 2. Materials and methods 2.1. Patient evaluation During the investigation, 191 patients were under consideration for PEP initiation or PEP continuance. Nearly all had suffered bite wounds from animals that were unvaccinated against rabies or had unknown vaccination histories. The exceptions were three family members who had direct skin contact with saliva from a mongoose after touching the family dog, but incurred no bites. Because most animals involved in these exposures had eluded capture, neither rabies diagnosis nor 10-day observation could be used to rule out rabies virus exposure to these patients. Exposure dates of the evaluated patients ranged from September 28, 2007 to August 3, 2008. Dogs were responsible for 153 (80%) exposures, cats were responsible for 31 (16%), and horses, a mongoose, and a pig were responsible for the remainder (4%). None of the patients had been previously vaccinated against rabies. 2.2. Selection and analysis of serostudy participants Of 191 patients, 53 (28%) had received one dose of RIG and at least one dose of HDCV or PCECV. After reviewing health department records and conducting telephone interviews, CDC and the PRDH determined that five patients had completed PEP, nine were currently receiving PEP on schedule, and one patient had moved away from Puerto Rico. These individuals were excluded from further evaluation. Recommendations for PEP continuance was made Table 1 Description of rabies PEP recipients who received one dose of RIG and at least one dose of HDCV or PCECV and consented to serological evaluation, Puerto Rico, 2008. No. of vaccine doses received No. of patients No. male (%) Median age in years (range) 1 2 3 4 Total 3 6 5 4 18 0 6 (100) 3 (60) 3 (75) 12 (67) 14 (8–43) 16 (2–72) 43 (5–52) 9 (4–21) 14.5 (2–72) PEP, postexposure prophylaxis; RIG, rabies immune globulin; HDCV, human diploid cell vaccine; PCECV, purified chick embryo vaccine. for four patients in the absence of serological testing because they had received only one dose and had sustained what appeared to be relatively high risk exposures, while PEP continuance was not recommended for two patients based on lower risk exposure histories. The PRDH knew of the existence of two other patients who had initiated PEP, but lacked records for these patients. The remaining 30 patients who had received less than five doses of vaccine were therefore considered to be candidates for serological testing. Of these 30 patients, 18 (60%) consented to have blood drawn to determine their serum virus neutralizing antibody level using the rapid fluorescent focus inhibition test (RFFIT). PEP continuance was recommended for the non-consenting individuals. The RFFIT was conducted as previously described [11]. 2.3. Interpretation of serological results A patient who failed to exhibit a serum neutralizing antibody value equal to or greater than the WHO standard of 0.5 IU/ml [12] was advised to continue PEP until receipt of five vaccine doses in accordance with the 2008 ACIP recommended schedule. However, serum exhibiting complete virus neutralization at the 1:5 dilution was considered an objective indicator of an adequate immune response, in accordance with the ACIP and by test definition [1]. Meeting the ACIP standard value had no influence on recommendations for PEP continuance. 3. Results Of the 18 individuals who consented to serology, all had received human RIG (on day 0), three (17%) had received only one vaccine dose, six (33%) had received two doses, five (28%) had received three doses, and four (22%) had received four doses. Table 1 describes dose groups by sex and median age. The majority (67%) of patients were male and median age was 14.5 years. As shown in Table 2, the median number of days between the last dose received and serum collection was 147 days with a range of 24–215 days. Ten (56%) of the eighteen recipients had values less than 0.5 IU/ml. Of these 10 individuals, 8 (80%) had received only one or two vaccine doses. One recipient in the 3-dose vaccine group and one recipient in the 4-dose group exhibited values less than 0.5 IU/mL (0.43 and 0.12 IU/mL, respectively). The number of days from last vaccine dose to serum collection for these individuals was 143 and 145, respectively. Wilcoxon–Mann–Whitney comparison between 3- and 4-dose patients with values below 0.5 IU/mL and same-dosed counterparts who exhibited values greater or equal to 0.5 IU/mL showed no significant differences with respect to the median days from last vaccine dose (median of 133 days [range 24–154] for 3-dose recipients and 168 days [range 126–215] for 4-dose recipients; p = 1.0 and p = 0.4, respectively). In total, completion of PEP was recommended to 10 (56%) patients who had values lower than 0.5 IU/mL. These patients were advised to complete PEP in accordance to the ACIP-recommended schedule from the point that PEP had been discontinued. Of the 6525 K. Robertson et al. / Vaccine 28 (2010) 6523–6526 Table 2 Serology RFFIT results of rabies PEP recipients who had one dose of RIG and at least one dose of HDCV or PCECV, Puerto Rico, 2008. No. of vaccine doses received No. of patients Median days from last dose to serum collection (range)a Geometric mean titerb (range) No. (%) with titer ≥ 0.5 IU/ml No. (%) exhibiting 100% VNc 1 2 3 4 Total 3 6 5 4 18 94 (78–110) 180 (154–185) 145 (24–154) 155.5 (126–215) 147 (24–215) 0.06 (<0.05–0.09) 0.19 (<0.05–0.57) 2.93 (0.43–12.40) 1.13 (0.12–13.3) 0.73 (<0.05–12.40) 0 (0) 1 (17) 4 (80) 3 (75) 8 (44%) 0 (0) 2 (33) 5 (100) 4 (100) 11 (61) RFFIT, rapid fluorescent focus inhibition test; PEP, postexposure prophylaxis; RIG, rabies immune globulin; HDCV, human diploid cell vaccine; PCECV, purified chick embryo vaccine. a Information on the date of last vaccine dose received was lacking for one 1-dose recipient and two 2-dose recipients; values shown therefore only reflect available data. b Geometric mean titer (IU/mL) calculated only from samples equal to or greater than 0.05 IU/mL; titer of reference serum used was equal to105 IU/mL. c 100% VN = 100% virus neutralization at the 1:5 dilution. eight patients not recommended for PEP continuance, one (12%) had received two doses of vaccine, four (50%) had received three doses, and three (38%) had received four doses. Evidence of adequate seroconversion as determined by the ACIP standard were exhibited by 11 (61%) patient samples, with all five of the 3-dose recipients and all four of the 4-dose recipients showing seroconversion. Of the six 2-dose recipients, only two (33%) showed 100% virus neutralization at the 1:5 dilution. None of the 1-dose recipients showed evidence of seroconversion. 4. Discussion In this study, all PEP recipients who had received either three or four vaccine doses exhibited seroconversion, based on the ACIP standard. In both groups, the median number of days between the last vaccine dose and serum collection was relatively long (∼5 months), which suggests that a significant decay in antibody titer does not occur readily in the absence of a fourth or fifth vaccine dose. These findings, combined with previous studies, affirm that a PEP regimen composed of fewer than five vaccine doses launches a prominent immunological response against rabies. No ‘seroprotective’ value has been established for rabies prophylaxis. The WHO serological criterion of 0.5 IU/mL was used as a basis for not recommending the administration of additional vaccine doses. Because discontinuance of PEP is nonstandard practice, the arbitrary WHO cutoff was used as means of fulfilling a higher burden of proof that a recipient of partial PEP had generated an adequate immune response, as it may be perceived as a more conservative estimate of immunity than the ACIP standard. Neither threshold, however, has been found to be inferior to one another as a basis for predicting PEP effectiveness in humans. All healthy vaccinated patients seroconverted against rabies virus by day 14, after the receipt of only three doses of vaccine. This report describes an approach to assessing patient need for rabies PEP continuance that utilized both exposure evaluation and serological analysis. This strategy was used to conserve vaccine during an emergency situation precipitated by the confluence of organizational changes within the PRDH with marked decline in the availability of human rabies vaccine. The 2008 ACIP guidelines do not advocate the routine use of serology in making decisions related to PEP cessation [1]. Use of serological analysis to assign vaccine need during vaccine limitations or shortages, however, may have utility in conjunction with other operative strategies to both minimize unnecessary vaccine use and ensure thorough exposure assessment. No cases of human rabies have been reported among any of the patients evaluated in the described investigation, including those who had received significantly less than five doses of rabies vaccine and those who did not receive rabies PEP until several weeks after exposure. However, none of these patients were exposed to confirmed rabid animals. Consequently, the effectiveness of a reduced regimen cannot be concluded with certainty from the absence of rabies cases among these patients, as exposure to rabies virus could not be assessed definitively. In this study, evidence of non-inferiority was restricted to serological surrogates rather than clinical outcomes. However, we consider this limitation to be minor since data are lacking which suggests that either current WHO or ACIP standards are unreliable indicators of immunity. Small sample size and lack of data at multiple time points for each patient are additional limitations that may impact on the generalizability of our results. Minor deviations from the recommended vaccine schedule of days 0, 3, 7, 14, and 28 were also observed in patients with respect to the absolute date that vaccine doses were administered. The precise effect that these deviations may have on our results is unknown. The results of this investigation help to challenge the assumption that rabies prevention necessitates a 5-dose vaccine regimen. Given the considerable expense associated with PEP biologics and their administration, reducing the recommended number of vaccine doses associated with PEP may produce appreciable costsavings to both patients and third-party payers, either through obviating the direct costs that currently come with paying for five vaccine doses or through lowering the indirect costs associated with doctor’s fees, lost wages, and travel expenses. The intake of fewer vaccine doses may also help limit the risk and severity of adverse reactions to which patients are subjected. In particular, these include the hypersensitivity reactions that have been reported in approximately 6% of patients receiving booster vaccination with HDCV [13]. Acknowledgement We wish to thank Mildred Rivera and Rafael Gonzalez for their assistance in this study. 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