When a person has been previously immunized with a PrEP series of three doses of rabies vaccine, the current recommendations for PEP include the administration of two booster doses of a WHO-recommended tissue culture vaccine. It is neither necessary nor recommended to administer RIG to individuals that have received a tissue culture vaccine previously. The question as to whether the time interval between primary vaccination series and the PEP booster series following an exposure has an influence on the ability of a patient to elicit an anamnestic response is an important concern for public health officials that may be considering the use of PrEP to protect populations living in areas with a high risk of exposure to rabies. In this study we investigated the anamnestic response in subjects that had received a two booster dose series of PEP one, three, and five years after the primary PrEP immunization, and we have confirmed that an adequate and rapid immune response occurred in all subjects.
Interestingly, RVNA concentrations and the percentage of patients that produced adequate titers did not change significantly over the years. In subjects that had been vaccinated five years previously, approximately the same RVNA concentrations were observed as in subjects that had been vaccinated one and three years earlier. After the two-booster dose PEP series, a comparable immune response was observed in all subjects regardless of the time elapsed since their initial PrEP series. A more relevant consideration is how many doses were included in the initial primary vaccination series: those subjects that received a three-dose primary PrEP series had higher levels of RVNA concentrations and higher booster responses than subjects that received only a two-dose primary PrEP series (). However, although GMTs of RVNA concentrations in the group that received a two-dose PrEP series were significantly lower throughout the study, in this group all subjects achieved adequate RVNA concentrations above 0.5
IU/mL, when two booster doses were given up to five years after primary vaccination. The fact that all subjects reached adequate RVNA concentrations by day 14, regardless of the time interval between primary series, and booster doses or the number of doses in the primary series is reassuring. However, the overall lower RVNA concentrations in the 2-dose group resulted in a lower percentage of adequate RVNA concentrations on day 7. In particular, in the 2-dose group adequate immune responses were only seen in 73% of children (3-year data), compared to 97–100% in the 3-dose groups. This leaves a vulnerable period of a few days in more than few subjects after a 2-dose primary vaccination series. Whether this would lead to treatment failure and development of rabies remains questionable. In PEP of previously unvaccinated subjects, adequate RVNA concentrations do not develop before day 14 either. Clearly here RIG is recommended to cover the lag period. However, in reality RIG is only administered in 2 to 10% of all cases, where it would be indicated [18
], and treatment failures are seen extremely rarely. To be on the safe side, however, as administration of RIG is not considered necessary or recommended for previously vaccinated subjects, a 3-dose primary vaccination regimen might be considered more suitable for individual protection.
Additionally the question how to prove previous vaccination has to be discussed. It is not uncommon that children or parents forget about the vaccines that they had been given. A serologic testing may not be a suitable method for proof of earlier vaccination. Such testing may not be available everywhere, is quite expensive, and—most critically—would provide results too late for a decision whether to give booster doses without RIG or whether to start a complete series of PEP, including RIG when indicated. Therefore, a system of documentation of each vaccination in a booklet is preferred. As a matter of fact, in absence of documented proof of vaccination, a full PEP course including administration of RIG would be required.
The WHO recommends that diagnostic laboratory workers, rabies researchers, and other people at continuous risk (where rabies virus is present continuously, often in high concentrations, and where specific exposures to rabies are likely to go unrecognized) should have their serological titers evaluated every six months for the presence of RVNA and receive a single booster vaccination when their RVNA concentrations fall below 0.5
]. For the general population living in endemic countries, it is sufficient to receive a routine ID booster series with 0.1
mL of PCECV without routine serology testing, which is expensive and difficult to perform. Due to the fact that immune memory is established in persons that have been vaccinated with a TCV, an anamnestic immune response is induced after a PEP-booster series using 0.1
mL of a TCV (PCECV) ID booster doses, as demonstrated in this study up to five years after completion of the primary vaccination.
The results of this study are in line with results from another study investigating abbreviated and less doses intradermal pre-exposure vaccination schedules. In one of the study arms, Khawplod and coworkers administered two ID doses at two sites on a single visit as primary vaccination, using PCECV or PVRV. Upon two ID booster doses (Day 0 and 3) one year later, all subjects elicited anamnestic immune responses and adequate RVNA concentrations [19
A striking additional finding in our study was that 12 of 703 children (1.7%) were actually exposed to rabies by potentially rabid animals during the study period. These were given appropriate PEP as predefined in the study protocol, and they were further excluded from serology analyses but were followed for a period of one year. All remained healthy during the observation period. The high number of exposures clearly shows that rabies is an endemic threat to children in Thailand.