False-Positive Human Immunodeficiency Virus Seroconversion Is Not Common following Rabies Vaccination

The risk of rabies infection in humans is primarily controlled by widespread vaccination of domestic dogs and cats and, more recently, by vaccination of wildlife reservoirs (1). In contrast, vaccination of humans against rabies is uncommon and is limited to individuals with a significant risk of occupational exposure to rabies virus (1). Veterinarians have a high risk of exposure to rabid animals, particularly during clinical examination of animal patients with early, nonclassical signs of rabies infection. Consequently, veterinary students are commonly vaccinated against rabies virus prior to entering clinical training. The most common vaccination protocol is an initial immunization followed by two booster immunizations, all using a killed vaccine.

A previous study reported that the vaccination of an animal care worker by means of this protocol induced a false-positive human immunodeficiency virus (HIV) seroconversion, as detected 16 days following the third immunization by an enzyme-linked immunosorbent assay (ELISA) measuring antibody against HIV (3). Testing of serum samples collected 2, 3, and 8 months after the final rabies virus vaccination with the HIV ELISA revealed a reversion to seronegative status, and the HIV-negative status of the individual was confirmed by Western blot analysis and PCR (3). Not surprisingly, the likelihood of seroconverting to HIV-positive status, even if transiently, is a significant factor that is considered by veterinary students when deciding whether to be vaccinated against rabies. To address this concern, we replicated the conditions that led to the previously described false-positive HIV seroconversion by testing sera from veterinary students prior to and 16 days after the final booster immunization of the rabies vaccine series.

Thirteen Washington State University veterinary students, 12 females and 1 male (age range, 22 to 45 years), volunteered for the study. All individuals were considered at low risk of exposure to HIV based on their responses to a questionnaire regarding behaviors associated with increased risk of exposure. Serum obtained prior to the first immunization was collected from each individual, and all sera were negative when tested with the Genetic Systems HIV ELISA (Bio-Rad Laboratories). The individuals were then vaccinated with rabies virus vaccine (Connaught Laboratories) on day 0 and received booster immunizations on days 7 and 21. Serum was again obtained from each individual 16 days following the final booster immunization and was tested with the HIV ELISA. All sera were negative.

The occurrence of no false-positive seroconversions among 13 individuals vaccinated and tested by use of the identical protocol and reagents as those that resulted in the previously reported false-positive reaction is consistent with the conclusion that seroconversion to HIV-positive status is an infrequent event following rabies vaccination. Our data are in agreement with those of a previously reported study in which paired serum samples from 50 human rabies vaccinates were tested by HIV ELISA and were all found to be negative (4). However, it is important to note that these studies, either individually or combined, do not have the statistical power to identify a slightly increased risk of HIV seroconversion following rabies vaccination compared to the risk in the general, presumably non-rabies-vaccinated, population. The low prevalence of initial false-positive seroconversions, 0.08% in the general population (based on a sample of 8,293 random donors [Bio-Rad Laboratories Blood Virus Division, Redmond, Wash.]), results in a less than 50% probability (power) of detecting a twofold increase in the number of false-positive HIV seroconversions in rabies vaccinates; this probability does not increase until the sample size is between 4,800 and 9,600 samples (5). The low number of humans vaccinated against rabies virus each year precludes the possibility of testing a sample size that is large enough to identify a slight increase in risk. However, a very high rate of false-positive seroconversion, as would be expected in a true cross-reaction due to the sharing of a B-cell epitope by HIV and rabies virus (2), would more likely be detected using the small sample sizes examined here and reported previously (4). By using the combined sample size of 63 rabies vaccinates from both studies, the probability of detecting a false-positive seroconversion would be >50 and >99%, respectively, if the risk were increased 16- and 100-fold (5).

It is unclear whether the previously reported false-positive seroconversion reflects a true cross-reaction due to a shared B-cell epitope (2) or results from acute-phase reactants induced by the multiple-immunization series. Both scenarios could lead to a transient seropositive result immediately following the vaccination series and then a reversion to negative status as either the cross-reactive antibody titer declined below the ELISA detection limit or the acute-phase reactant level returned to normal. The HIV-negative status of the vaccinates in this study, which used the same timing as that reported previously for the false-positive seroconversion, suggests that the series of multiple vaccinations does not consistently induce high levels of acute-phase reactants that generate a false-positive result in the HIV ELISA. Although HIV type 1 gp120 and rabies virus glycoprotein share a sequence (2), this sequence does not seem to induce a consistent cross-reactive response.

In summary, false-positive seroconversion to HIV should not be considered a common event following a series of multiple rabies vaccinations as none of the 63 vaccinates examined in either the previous (4) or the present study developed positive reactions in the HIV ELISA. Compared with the risk of rabies infection, which is almost always fatal (1), concern about transient seroconversion to HIV-positive status, which is rare, should not dissuade at-risk individuals, such as veterinary students, from receiving prophylactic rabies vaccination.