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BCG and Other Vaccines
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Correlates of protection studies have cast doubt on the sufficiency of the cell-mediated immune response to confer protection by vaccination.130 Although the vaccine candidate MVA85A was immunogenic, inducing a robust and durable polyfunctional CD4+ T-cell response, it did not demonstrate protective efficacy in a recent phase IIb trial.131 The key to a successful TB vaccine may lie in the harnessing of humoral immunity in concert with a more potent cell-mediated response.
Bacille Calmette–Guerin and Prospects for New Vaccines against Tuberculosis
Published in Peter D O Davies, Stephen B Gordon, Geraint Davies, Clinical Tuberculosis, 2014
The other virus being developed in TB is MVA. MVA is known to be a potent vector for boosting cellular immunity and was administered at the end of the smallpox eradication campaign to over 100,000 subjects in Germany with an excellent safety record [93]. A recombinant MVA expressing Antigen 85A was the first new subunit vaccine to enter into clinical trials in 2002 and has since been evaluated in several phase I/IIa clinical trials including in M. tuberculosis latently infected subjects and in HIV-infected subjects [94–97]. These trials demonstrate this vaccine candidate induces antigen-specific CD4+ T cells and some class I restricted CD8+ T cells [98–100]. In preclinical animal models, MVA85A can improve BCG-induced protection [45,66,101,102]. This vaccine candidate is currently being evaluated in two phase IIb proof-of-concept efficacy trials, one in BCG-vaccinated South African babies and one in HIV-infected adults in South Africa and Senegal (ClinicalTrials. gov Identifiers: NCT00953927 and NCT01151189).
Inhaled therapeutics against TB: The promise of pulmonary treatment and prevention strategies in the clinic
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Dominique N. Price, Nitesh K. Kunda, Elliott K. Miller, Pavan Muttil
Despite the many advantages of pulmonary administration of vaccines, the majority of the current vaccine candidates in development vary in antigen and carrier and are almost exclusively administered systemically. MVA85A was the first study to show safety and immunogenicity in BCG-vaccinated healthy adults when delivered as aerosols (107). This phase I, double-blinded trial was performed (NCT01497769) to compare the safety and immunogenicity of MVA85A when administered as an aerosol (107). The primary outcome of this study was safety evaluated by assessing vaccine-related local and systemic adverse events. The secondary outcome of the study was immunogenicity evaluated by assessing cell-mediated immunity markers in the blood and bronchoalveolar lavage fluid (BALF). Intradermal administration had mild local injection-site reactions, whereas the aerosol adverse events were mild. Systemic adverse events did not differ between the immunization groups, with mild fatigue and mild to moderate headache as the most common symptoms. Both routes of vaccination induced MVA CD4+ and CD8+ T cell responses, with the aerosol group reporting higher CD4+ T cell responses than the intradermal group. The aerosol group induced a higher number of Ag85A-specific CD4+ T cell cytokines. The study concluded with the observation that aerosol administration induced equally strong systemic immune responses and significantly stronger BALF immune responses compared to intradermal vaccination (107). Based on the promising results from this study, another aerosol trial is underway to fully characterize the mucosal and systemic immune responses to the MVA85A vaccine and to evaluate safety in latent TB patients (NCT02532036).
Mucosal delivery of tuberculosis vaccines: a review of current approaches and challenges
Published in Expert Review of Vaccines, 2019
Elena Stylianou, Matthew J. Paul, Rajko Reljic, Helen McShane
Although the efficacy result from the first prophylactic vaccine in clinical trials, MVA85A, was disappointing, this vaccine has an excellent safety record [90–93]. The safety of MVA85A allowed its aerosol administration in humans, the first TB vaccine to be evaluated using this route of administration in humans [94]. MVA85A was administered in BCG-vaccinated healthy volunteers either via aerosol or intradermally. Volunteers that received the aerosol vaccination had stronger mucosal and equally strong systemic responses compared to the intradermal group. Interestingly the mucosal route had a lower level of systemic humoral anti-vector responses. In a follow up phase I experimental medicine study, it was hypothesized that the lower levels of anti-vector responses would result in improved Ag85A-specific responses in a sequential homologous prime-boost immunization [95]. Surprisingly there was no boosting of antigen-specific responses in the aerosol-intradermal group, in contrast to the intradermal-aerosol group were a boosting effect was detected. However, whereas aerosol followed by intradermal MVA85A was well tolerated, the intradermal-aerosol group was associated with transient but significant respiratory side effects. The reasons behind these observations are not known but these data are important to the development of aerosolized vaccines. It is worth noting that preliminary data from the aerosol administration of MVA85A to adults with latent TB were not associated with any safety concerns (ClinicalTrials.gov NCT02532036). In mice, intranasal administration of MVA was able to induce iBALT in the lungs [96].
Synergy between Th1 and Th2 responses during Mycobacterium tuberculosis infection: A review of current understanding
Published in International Reviews of Immunology, 2019
At present, there are thirteen candidate vaccines against TB in different stages of clinical trials, probably the highest number of candidate vaccines under evaluation in the history of TB [25]. The main criterion for selection of the current candidate vaccines against TB is based on the production of IFN-γ by CD4 T cells. This is based on animal studies that have shown the importance of IFN-γ producing CD4+ T cells in protecting against TB [26,27]. One such a candidate vaccine is MVA85A. MVA85A is comprised of the attenuated poxvirus modified Vaccinia Ankara (MVA), that expresses the Mtb antigen 85 A (Ag85A), which is a secreted protein of Mtb. Ag85A induces high frequency of T cell responses and is a candidate vaccine in phase II clinical trials [28]. Using BCG as priming immunization in BALB/c mice and then boosting these mice with MVA85A induces higher levels of both antigen specific CD4+ and CD8+ T cells [29]. However, macaque monkeys given MVA85A, in addition to BCG vaccine, had higher mortality than those given BCG alone. Moreover, it was not beneficial when tested in large clinical trial in infants [30,31].
Health economic evaluation of current vaccination strategies and new vaccines against tuberculosis: a systematic review
Published in Expert Review of Vaccines, 2019
Afifah Machlaurin, Simon van der Pol, Didik Setiawan, Tjip S. van der Werf, Maarten J Postma
Our results indicate that a new, improved vaccine that would provide greater protection in older children and adults would be a more cost-effective strategy. This finding is in line with those of another review study on modeling a future TB vaccine, which predicts that a novel TB vaccine targeting older age groups (with pre-exposure and/or post-exposure efficacy) would have a better and more rapid epidemiological impact than would neonatal vaccination only [52]. Most new vaccines have been intended as prime boosters and applied in adolescence, with the expectation that they would provide additional protection beyond that of the current BCG vaccine, with the drawbacks associated with its waning effects [53]. The only new vaccine assessed in the studies analyzed in this review is MVA85A. According to a randomized controlled trial, however, MVA85A has no significant efficacy [54]. Meanwhile, currently, two potential new TB vaccines have entered phase 2b trials. Firstly, H4:IC31 which showed a moderate efficacy of 30.4% against M. tuberculosis infection in a high-transmission setting [51]. Secondly, M72/AS01E which showed a vaccine efficacy of 50.4% against progression of M. tuberculosis infection into active pulmonary TB [55]. The modeling studies in this review consistently indicate that the new vaccine would be cost-effective if its vaccine efficacy against TB were to be at least around 40% [30,32,33]. Given that we found vaccine efficacyto be one of the key drivers of the cost-effectiveness of vaccines, further research and economic evaluations of the two aforementioned new vaccines are warranted. Further (cost-effectiveness) research would also need to focus on the other main drivers of cost-effectiveness: the duration of protection, especially within the adult population, and the pricing of the new vaccines.