Protection against Tetanus by Needle-Free Inoculation of Adenovirus-Vectored Nasal and Epicutaneous Vaccines

Abstract

The effectiveness of vaccination programs would be enhanced greatly through the availability of vaccines that can be administered simply and, preferably, painlessly without the need for timed booster injections. Tetanus is a prime example of a disease that is readily preventable by vaccination but remains a major threat to public health due to the problems associated with administration of the present vaccine. Here we show that a protective immune response against live Clostridium tetani infection in mice can be elicited by an adenovirus vector encoding the tetanus toxin C fragment when administered as a nasal or epicutaneous vaccine. The results suggest that these vaccination modalities would be effective needle-free alternatives. This is the first demonstration that absorption of a small number of vectored vaccines into the skin following topical application of a patch can provide protection against live bacteria in a disease setting.Tetanus continues to be a threat to public health with more than half a million fatalities each year being associated with infection with Clostridium tetani (23). Due to the ubiquitous distribution of the causal agent, vaccination is the most effective medical intervention for protection of the public against this deadly disease. The effectiveness of the vaccine is due, at least in part, to the fact that the sequences of the neurotoxin molecules are conserved among different strains of C. tetani, which permits elicitation of a protective immune response against all C. tetani strains through the use of a single vaccine (23). The effectiveness of the vaccine is limited, however, by the needle-based delivery method currently in use. Effective protection requires injection of three consecutive doses of the tetanus toxoid vaccine (16). Moreover, booster injections must be administered periodically during adulthood to compensate for the age-related decline in antitoxin levels (16). In developing countries, vaccine coverage against this disease is generally low due to failure to follow up as well as a lack of the trained medical personnel and facilities required for administration of the vaccine. In developed countries, although vaccine coverage in childhood is high, there is a general lack of compliance of adults with recommended schedules for booster injections (16). These factors have led to the realization that tetanus vaccination programs would be improved significantly worldwide through the development of low-cost, needle-free vaccines.Needle-free vaccination requires the development of novel vaccines that can be administered safely and effectively. Several routes of administration are being considered. Both nasal and oral immunizations have been shown to be effective in eliciting an immune response against a number of pathogens. An alternative new modality is noninvasive vaccination onto the skin (NIVS) by topical application of epicutaneous vaccines (8,10,11,17,18,22), which would offer a greater safety margin and eliminate the discomfort associated with injections. Prior to our ...

Enabling topical immunization via microporation: a novel method for pain-free and needle-free delivery of adenovirus-based vaccines

“…According to this approximation, we are exposing mice to 1 Â 10 7 pfu rdAd following application of the highest vaccine dose. In a study where the rdAd vaccine was applied to skin that was decornified by gentle brushing, 15 seroconversion occurred at doses of 10 8 particles (approx. 10 6 pfu) and high-level protection from challenge (480%) required at least 10 9 Figure 7 Microporation can greatly enhance the immunogenicity of adenovirus vaccines carrying weak antigens.…”

“…Topical administration should prove less complicated and, indeed, previous reports have demonstrated that rdAds can successfully immunize mice following topical application to de-cornified skin. [13][14][15] Removal of the cornified skin layer involved user-specific methods such as depilatories, soft brushing and adhesives. We expect microporation to provide a standardized, painless method to prepare the skin for topical delivery of rdAds.…”

A differential proteome in tumors suppressed by an adenovirus‐based skin patch vaccine encoding human carcinoembryonic antigen

“…Briefly, young (3 months old) female Balb/c mice (Jackson Laboratory, Bar Harbor, ME, USA) were epicutaneously vaccinated with 100 μL of 1 × 10 8 PFU of adenovirus (E1/E3-defective non-replicated adenovirus type 5) which contained a cytomegalovirus early promoter-directed tetanus toxin C fragment (AdCMV-tetC) (constructed as described [13]) or human carcinoembryonic antigen gene (AdCMV-hCEA) (kindly provided by Dr. Teresa Strong, Gene Therapy Center at University of Alabama at Birmingham, AL, USA). The mice were anesthetized by administrating 10 mg of ketamine and 1.5 mg of xylazine per 100 g of body weight.…”

“…This ballistic delivery can introduce DNA directly into dermal antigen presenting cells (APC), which sub-sequently migrate into local lymph nodes and prime immune responses [10,11]. It has been reported that most of the immunocompetent cells including APC is confined to the epidermis rather than the dermal layer of the skin [12,13]. This notion inspired us to develop skin patch vaccines via application of the adenovirus vedors upon the surface of the mouse skin.…”

“…This notion inspired us to develop skin patch vaccines via application of the adenovirus vedors upon the surface of the mouse skin. We have demonstrated that the adenovirus-based skin patch vaccines which encode a variety of antigens including C fragment tetanus toxin [13], hemagglutinin, and CEA [3] can evoke pronounced skin immunity. The administration of a traditional vaccine usually requires one or more needle injections performed by medical personnel.…”