Intranasal Boosting with an Adenovirus-Vectored Vaccine Markedly Enhances Protection by Parenteral Mycobacterium bovis BCG Immunization against Pulmonary Tuberculosis

Abstract

Parenterally administered Mycobacterium bovis BCG vaccine confers only limited immune protection from pulmonary tuberculosis in humans. There is a need for developing effective boosting vaccination strategies. We examined a heterologous prime-boost regimen utilizing BCG as a prime vaccine and our recently described adenoviral vector expressing Ag85A (AdAg85A) as a boost vaccine. Since we recently demonstrated that a single intranasal but not intramuscular immunization with AdAg85A was able to induce potent protection from pulmonary Mycobacterium tuberculosis challenge in a mouse model, we compared the protective effects of parenteral and mucosal booster immunizations following subcutaneous BCG priming. Protection by BCG prime immunization was not effectively boosted by subcutaneous BCG or intramuscular AdAg85A. In contrast, protection by BCG priming was remarkably boosted by intranasal AdAg85A. Such enhanced protection by intranasal AdAg85A was correlated to the numbers of gamma interferon-positive CD4 and CD8 T cells residing in the airway lumen of the lung. Our study demonstrates that intranasal administration of AdAg85A represents an effective way to boost immune protection by parenteral BCG vaccination.Tuberculosis (TB) is the second leading cause of death by infectious disease worldwide. Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been the vaccine of choice given to humans via the skin for over 80 years and has shown variable efficacies of between 0 and 80% in clinical studies (25). In spite of this fact, over 80% of the world population are BCG vaccinees; this vaccine is still being utilized and will likely continue to be utilized in the majority of the world as a part of childhood vaccination programs because of its efficacy in preventing adolescent and disseminated forms of TB, despite the fact that BCG has been shown to have variable efficacies in preventing adult pulmonary tuberculosis (1, 6). Its limited success in control of adult TB has been attributed at least in part to the fact that immune protection by BCG wanes within 10 to 15 years. Much of the past effort has focused on modifying the current BCG vaccine or identifying new vaccine platforms (11,17,22). However, these strategies are unlikely to accomplish long-term TB protection in humans. Furthermore, replacement of the currently used BCG with a different vaccine platform is increasingly considered an unrealistic goal because of the wide clinical usage of BCG and because any phase III clinical vaccine trial would not ethically be allowed to withhold BCG vaccination (12,26). Therefore, the development of strategies that aim to boost BCG-mediated protection represents a priority (15). In this regard, BCG has been shown to be an ineffective booster vaccine for itself and may even be deleterious to protection against TB, as previously shown in clinical and experimental studies (2,5,8). Increasing evidence suggests that effective booster vaccines for BCG immunization ought to be nonmycobacterial (boosters heterologous to BCG) and may inc...

Vaccine against tuberculosis: what’s new?

“…Intranasal administration enhanced a better protection than intramuscular in both settings [33,34]. In guinea pigs, both intranasal and intramuscular vaccination were protective against pulmonary TB infection.…”

Impact of Recombinant Adenovirus Serotype 35 Priming versus Boosting of aPlasmodium falciparumProtein: Characterization of T- and B-Cell Responses to Liver-Stage Antigen 1

“…In addition, the immune response can be synergistically improved or even redirected when combining different types of vaccines (15,34,35). A number of studies have indicated that recombinant adenoviral (rAd) vectors are highly suitable as a component of a heterologous prime-boost regimen with other types of vaccines, such as DNA (32,53,54), poxvirus vectors (9,20), or Mycobacterium bovis BCG (46,55), leading to enhanced immunogenicity and protection in relevant models. rAd vectors are particularly suited for the induction of strong CD8 ϩ T-cell responses due to intracellular expression of the transgene built in their genome and efficient routing of expressed protein toward the class I presentation pathway.…”

Current status of new tuberculosis vaccine in children

“…Primary data showed thatAdAg85A provided promising protection against TB infection in mice when priming as booster vaccine for BCG when administered intranasally. 62,63 Compared with intramuscular injection, intranasal administration induced stronger CD4 and CD8 T cell responses. 63,64 More recently, a literature from Mu et al reported that a new intranasally bivalent adenovirus-vectored vaccine expressing both Ag85A and TB10.4 antigen conferred a significantly improved level of protection against M. tuberculosis challenge comparable to Ag85A alone or BCG immunization.…”

“…62,63 Compared with intramuscular injection, intranasal administration induced stronger CD4 and CD8 T cell responses. 63,64 More recently, a literature from Mu et al reported that a new intranasally bivalent adenovirus-vectored vaccine expressing both Ag85A and TB10.4 antigen conferred a significantly improved level of protection against M. tuberculosis challenge comparable to Ag85A alone or BCG immunization. 65 In a Phase I clinical trial evaluating safety and immunogenicity of AdAg85A administered intramuscularly, the vaccine was found to be safe and well tolerated.…”