Recent Developments in Tuberculosis Vaccines

Dessislava Marinova; Jesus Gonzalo-Asensio; Nacho Aguilo; Carlos Martin


Expert Rev Vaccines. 2013;12(12):1431-1448. 

In This Article

Rethinking Vaccination Route

According to meta-analysis studies, the inconsistent efficacy of BCG is thought to be due to waning vaccine-induced immune responses with age which can reach an average of 14% overall efficacy after 10 years.[134] As a result, a consensus is emerging that new vaccine strategies should be targeted for prevention of TB in adolescents and adults where incidence is relatively high.[133,135] Nevertheless, epidemiological data in countries with routine use of BCG show that the highest incidence of TB cases in HIV-negative individuals is comparable early in life between 0 and 4 years of age and in adolescents and adults, and it is lowest between 5 and 14 years of age reaching nadir at about 10 years of age.[136,137] These data suggest that there appears to be a natural susceptibility to TB, which BCG is not able to overcome regardless of age, and that it could be a question of quality rather than durability of the immune responses induced by BCG against the common form of the disease responsible for transmission.

One hypothesis for BCG inconsistent efficacy against MTB infection and disease is that circulating T-cell immunity induced upon vaccination (by intradermal route) is inadequate to reach the lungs on time when MTB infection occurs.[138] The natural route of MTB transmission is by aerosol and the nasal cavities are usually the first port of entry for the pathogen, while pulmonary mucosal tissues are the primary sites for establishment of infection.[70] The mucosal route of immunization has been suggested to have advantage over other routes to elicit protective immune responses in the lung, the site of primary TB infection.[139] Animal vaccination experiments by aerosol delivery of the BCG nanomicroparticle have shown significant reduction of bacterial burden in lung and spleen after MTB challenge as compared with parenteral BCG.[140] Moreover, in recent years, increasing number of new subunit strategies have been evaluated as heterologous boosts by the intranasal route to enhance efficacy of parentally primed BCG immune responses.[70] Ad5Ag85A, when administered intranasally but not intramuscularly, afforded better protection against M. tuberculosis aerosol challenge than cutaneous BCG and enhanced protection when given as a boost to BCG in both BALB/c mice and guinea pigs.[95,141,142] McMaster University, where the vaccine was conceptualized, plans to conduct a Phase I trial evaluating aerosol delivery of Ad5Ag85A.[209] Intranasal delivery of MVA85A significantly enhanced BCG-primed circulating immune responses and inhibited bacterial growth by up to 1.5 logs following aerosol MTB challenge in mice when compared with BCG alone.[143] Ad35/Aeras 402 showed efficacy against intranasal MTB challenge in two strains of mice by the intramuscular and intranasal routes.[97] Despite these promising data, the intranasal delivery of live vaccines carries serious safety risks inherent with this route (dissemination to the brain and potential lung disease in false-negative individuals with LTBI) and to date only the live influenza vaccine (Hib) is given intranasally in clinic. For future use of this route, extensive preclinical and clinical characterization with new TB vaccine boosts is imperative. In this context, the safety and immunogenicity of MVA85A delivered by the aerosol route to the lungs of macaques was recently published[144] and currently inhaled preparation of live MVA85A is currently being tested for safety and immunogenicity in a Phase I trial in healthy adults in the UK.[227]

There are two trends in TB vaccine development that warrant mentioning. First, there is a new interest in BCG and novel TB vaccines for prevention of infection (and not just prevention of disease). This concept was introduced at the 3rd Global Forum on TB Vaccines in Cape Town, and Aeras in collaboration with SATVI are planning a prevention of infection trial with the H4 vaccine and BCG in adolescents. Second, in addition to the very important issue of considering alternative vaccination routes such as mucosal, there are developments in improving the administration technique of intradermal BCG, which may also have implications for future novel vaccines, particularly for the intradermal route. For example, an ongoing trial at the SATVI site (funded by PATH and WHO) is comparing BCG administration via conventional syringe and needle to a needle-free jet injector device.[228] Other devices to aid vaccine administration such as intradermal needle adaptors have also been developed for use in the field.