Boosting BCG with Recombinant Modified Vaccinia Ankara Expressing Antigen 85A: Different Boosting Intervals and Implications for Efficacy Trials

Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
PLoS ONE (Impact Factor: 3.23). 02/2007; 2(10):e1052. DOI: 10.1371/journal.pone.0001052
Source: PubMed


OBJECTIVES To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination.

DESIGN There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naïve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime-MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG.

RESULTS MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination.

CONCLUSIONS The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here.

TRIAL REGISTRATION NCT00427453 (short boosting interval), NCT00427830 (long boosting interval), NCT00480714 (BCG alone).

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Available from: Helen A Fletcher
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    • "BCG-induced protection was enhanced by boosting with MVA85A in the mouse [91], guinea pig [92], and rhesus macaque models [93]. Additionally, MVA85A has been evaluated in human subjects, including healthy/BCG-vaccinated, BCG-naïve, latent Mtb, and human immunodeficiency virus-infected patients in phase I clinical trials at Oxford University (UK), since 2002 [94,95,96], and further in phase I and IIa clinical trials in the UK, South Africa, The Gambia and Senegal [97,98,99,100]. More recently, phase IIb clinical trials have evaluated the safety and efficacy of MVA85A in healthy/BCG vaccinated infants (Fig. 1) [101]. "
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    ABSTRACT: Tuberculosis (TB) remains a worldwide health problem, causing around 2 million deaths per year. Despite the bacillus Calmette Guérin vaccine being available for more than 80 years, it has limited effectiveness in preventing TB, with inconsistent results in trials. This highlights the urgent need to develop an improved TB vaccine, based on a better understanding of host-pathogen interactions and immune responses during mycobacterial infection. Recent studies have revealed a potential role for autophagy, an intracellular homeostatic process, in vaccine development against TB, through enhanced immune activation. This review attempts to understand the host innate immune responses induced by a variety of protein antigens from Mycobacterium tuberculosis, and to identify future vaccine candidates against TB. We focus on recent advances in vaccine development strategies, through identification of new TB antigens using a variety of innovative tools. A new understanding of the host-pathogen relationship, and the usefulness of mycobacterial antigens as novel vaccine candidates, will contribute to the design of the next generation of vaccines, and to improving the host protective immune responses while limiting immunopathology during M. tuberculosis infection.
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    • "We are developing a subunit viral-vectored vaccine, using Modified Vaccinia Virus Ankara (MVA) as a delivery system for the mycobacterial antigen 85A. This candidate vaccine is designated MVA85A and has been evaluated in a series of small Phase I safety and immunogenicity clinical trials in the UK since 2002 [6] [7] [8] [9]. The promising safety and immunogenicity of MVA85A led to further clinical trials in target populations in South Africa, The Gambia and Senegal [10] [11] [12] [13] [14] [15]. "
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    ABSTRACT: Background The development of a new, more effective vaccine against tuberculosis (TB) for use in healthy and HIV-infected adults, children and infants, remains a global health priority. MVA85A is a candidate tuberculosis vaccine designed to enhance immunity to the existing vaccine, Bacillus Calmette-Guerin (BCG). MVA85A entered clinical trials in 2002 and has now progressed to Phase IIb proof-of-concept efficacy trials in infants and HIV-infected adults in Africa.MethodsA detailed analysis was conducted of the cumulative safety data of intradermal delivery of MVA85A in 112 healthy adult subjects in a series of open label, single arm, non-controlled, Phase I safety and immunogenicity clinical trials in the UK. The trials differed with respect to previous mycobacterial exposure, vaccine regime and dose. Objective safety measures (local reaction size and body temperature) were evaluated for correlations with adaptive antigen-specific immune responses.ResultsAll subjects in the combined mid-dose group developed a local reaction, of which 92% were mild, 8% were moderate and no reactions were severe. Around 90% of subjects in each group reported at least one systemic adverse event, most commonly headache, myalgia, malaise, feeling feverish, fatigue and arthralgia. Of all systemic adverse events in the combined mid-dose group, 96% were mild, 3% were moderate and 1% were severe (but none of these were judged to be vaccine-related). Pre-vaccination mycobacterial exposure did not affect the adverse event profile. The size of local reaction and frequency of systemic adverse events increased with MVA85A vaccine dose. There were no documented fevers in the low-dose group, whilst 3% of subjects in the combined mid-dose group and 21% in the high-dose group had documented fevers. Peak local reactions were larger after a second poxvirus vaccination, but other local and systemic adverse events were comparable to a single MVA85A vaccination. No severe systemic AEs or serious adverse events in any group were judged to be vaccine-related. Local AEs compared favourably to BCG vaccine-induced local AE and systemic AEs after MVA85A vaccination were comparable to those after the live viral Yellow Fever vaccine in similar populations. There were no correlations found between local reaction size or body temperature and adaptive immune responses (measured by ex vivo interferon gamma Enzyme Linked Immunospot).Conclusions The candidate TB vaccine, MVA85A has been safely administered to over 100 healthy adults in the UK. Intradermal vaccination with MVA85A induced a transient, superficial reaction local to the injection site and mild short-lived viral symptoms. The local and systemic AE profile of MVA85A vaccination was comparable to published data of other intradermal vaccines and live viral vaccines respectively. Local reaction sizes and body temperature measurements did not correlate with the adaptive cellular immune response to MVA85A.
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    • "We have previously reported that recombinant Modified Vaccinia virus Ankara (MVA) expressing antigen 85A from MTB (MVA85A) is well-tolerated and enhances the frequency of antigenspecific IFN-␥ producing T cells in adults, children and infants previously vaccinated with BCG [4] [5] [6] [7] [8] [9] [10]. We have also shown that antigen specific T cells induced by MVA85A are highly polyfunctional , and can express IFN-␥, TNF-␣, IL-2, MIP1-␤ and IL-17 [11,12]. "
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