A study of more time-efficient and cost-effective pre-exposure rabies vaccination schedules to secure timely adequate protection prior to military deployment

Rabies is a zoonosis transmitted through the bite or scratch from an infected
animal (mainly wild or domestic canids). Infection, if left untreated, results
in progressive neurologic illness followed by death in all cases affected.
Illness and death can be averted by prompt cleaning of the wound and
administration of post-exposure prophylaxis (PEP).
PEP aims at achieving high levels of virus neutralizing antibodies (VNAbs),
>0.5 IU/mL preferably within 24 hours after exposure. This can be achieved in
two ways.
The first is by administration of the standard pre-exposure prophylaxis (PreP)
schedule which consists of 3 doses of the inactivated rabies vaccine on day
0,7,21 till 28, timely before deployment. In case of exposure, two inactivated
rabies vaccinations with an interval of 2 days are required with the first
given within 24 hours after exposure.
The second way, when no PreP has been administered, consists of administration
of human anti-rabies immunoglobulin (HRIG) within 24 hours after exposure,
followed by active immunization with five inactivated rabies vaccinations.

Usually, pre-exposure vaccination against rabies is advised to military
personnel deemed at risk of exposure to rabies infection during deployment
(i.e. in enzootic/epizootic areas).
Even though it is known that vaccination series induce long term immunologic
memory, several problems for implementation of rabies prevention in the
military setting exist. First, costs of the standard three-shot pre-exposure
series (¤135-150) may prohibit implementation of pre-exposure vaccination in
all situations where it is advised. Second, the pre-exposure vaccination using
the standard 3-injection schedule on days 0, 7 and 28 often results in
incomplete vaccination series prior to deployment, because vaccination is
initiated too late or can not be completed due to competition with other
pre-deployment preparation.
PEP with the use of HRIG and the 5-dose vaccination scheme, though effective,
is problematic in three ways. First, maintenance of a cold chain is required,
which can not always be achieved in operational settings. Also, the storage
life of HRIG is around one year, which is limited and leads to increased cost
of maintaining adequate supplies. Third, the 5-dose post-exposure vaccination
scheme is intensive and lengthy.
The problems discussed above call for exploration of alternatives in the form
of reduce-dosed, abbreviated pre-exposure vaccination schemes. Besides the
logistic benefit of shortened schedules, the schemes we aim to study are also
estimated to be less expensive than the above PEP scheme most often in use
today. See appendix.

Recent studies have shown that four 0.1 ml intradermal vaccinations given
simultaneously as a booster on day 0 elicit higher responses compared to the
standard two 1 ml intramuscular boosters given on days 0 and 3 (Tantawichien
1999, Khawplod 2002). This method has recently been approved by WHO in the
context of post-exposure boosting. We propose the use utilise this approach to
boost responses in a low-cost pre-exposure vaccination schedule.

1. To reduce the time required for pre-exposure rabies vaccination of military
personnel
2. To reduce costs of pre-exposure rabies vaccination of military personnel
3. To obtain a non-inferior immune response to a shortened, low-dosed scheme
compared to the standard scheme

Volunteers shall be randomly assigned to one of the study arms as depicted in
the two tables below:

Group 1: (control group) 2 x 0.1 ID vaccination on days 0, 7, 28 and a booster
at 1 year
Group 2: 2 x 0.1 cc ID vaccination on days 0, 7, 28 and a booster at 2 years
Group 3: 2 x 0.1 cc ID vaccination on days 0, 7 and a booster at 1 year
Group 4: 2 x 0.1 cc ID vaccination on days 0, 7 and a booster at 2 years
Group 5: 2 x 0.1 cc ID vaccination on days 0 and a booster at 1 year
Group 6: 2 x 0.1 cc ID vaccination on days 0 and a booster at 2 years

Previous studies have shown that local adverse events occur more often
following intradermal vaccination compared to intramuscular vaccination.
However, these effects are generally mild and self-limiting.
Potential risks of reduced schedules are that insufficient antibody titres are
be reached prior to booster vaccination at 12 or 24 months and that
participants may thus not be protected if deployed/travelling during the study
period. Risks for participants will be precluded by:
1. Excluding personnel likely to be deployed to a rabies endemic area within
the study period;
2. Providing full pre-exposure vaccination to participants for whom
pre-exposure vaccination is indicated, for example due to intended travel to a
rabies endemic area, if they have insufficient antibody responses at that
moment;
3. All participants with inadequate antibody responses at the end of the study
will be fully vaccinated.