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A five-antigen Esx-5a fusion delivered as a prime-boost regimen protects against M.tb challenge.

ABSTRACT: The development of tuberculosis (TB) vaccines has been hindered by the complex nature of Mycobacterium tuberculosis (M.tb) and the absence of clearly defined immune markers of protection. While Bacillus Calmette-Guerin (BCG) is currently the only licensed TB vaccine, its effectiveness diminishes in adulthood. In our previous research, we identified that boosting BCG with an intranasally administered chimpanzee adenovirus expressing the PPE15 antigen of M.tb (ChAdOx1.PPE15) improved its protection. To enhance the vaccine's efficacy, we combined PPE15 with the other three members of the Esx-5a secretion system and Ag85A into a multi-antigen construct (5Ag). Leveraging the mucosal administration safety of ChAdOx1, we targeted the site of M.tb infection to induce localized mucosal responses, while employing modified vaccinia virus (MVA) to boost systemic immune responses. The combination of these antigens resulted in enhanced BCG protection in both the lungs and spleens of vaccinated mice. These findings provide support for advancing ChAdOx1.5Ag and MVA.5Ag to the next stages of vaccine development.

SUBMITTER: Stylianou E

PROVIDER: S-EPMC10585038 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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A five-antigen Esx-5a fusion delivered as a prime-boost regimen protects against M.tb challenge.

Stylianou Elena E Pinpathomrat Nawamin N Sampson Oliver O Richard Alexandre A Korompis Marcellus M McShane Helen H

Frontiers in immunology 20231005

The development of tuberculosis (TB) vaccines has been hindered by the complex nature of Mycobacterium tuberculosis (M.tb) and the absence of clearly defined immune markers of protection. While Bacillus Calmette-Guerin (BCG) is currently the only licensed TB vaccine, its effectiveness diminishes in adulthood. In our previous research, we identified that boosting BCG with an intranasally administered chimpanzee adenovirus expressing the PPE15 antigen of M.tb (ChAdOx1.PPE15) i ...[more]

PMID: 37869008

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Project description:BackgroundAlthough vaccination is recommended for protection against invasive pneumococcal disease, the frequency of pneumococcal pneumonia is still high worldwide. In fact, no vaccines are effective for all pneumococcal serotypes. Fusion pneumococcal surface protein A (PspA) has been shown to induce a broad range of cross-reactivity with clinical isolates and afford cross-protection against pneumococcal challenge in mice. Furthermore, we developed prime-boost-type mucosal vaccines that induce both antigen-specific IgG in serum and antigen-specific IgA in targeted mucosal organs in previous studies. We investigated whether our prime-boost-type immunization with a fusion PspA was effective against pneumococcal infection in mice and cynomolgus macaques.MethodsC57BL/6 mice were intramuscularly injected with fusion PspA combined with CpG oligodeoxynucleotides and/or curdlan. Six weeks later, PspA was administered intranasally. Blood and bronchoalveolar lavage fluid were collected and antigen-specific IgG and IgA titers were measured. Some mice were given intranasal Streptococcus pneumoniae and the severity of infection was analyzed. Macaques were intramuscularly injected with fusion PspA combined with CpG oligodeoxynucleotides and/or curdlan at week 0 and week 4. Then, 13 or 41 weeks later, PspA was administered intratracheally. Blood and bronchoalveolar lavage fluid were collected and antigen-specific IgG and IgA titers were measured. Some macaques were intranasally administered S. pneumoniae and analyzed for the severity of pneumonia.ResultsSerum samples from mice and macaques injected with antigens in combination with CpG oligodeoxynucleotides and/or curdlan contained antigen-specific IgG. Bronchial samples contained antigen-specific IgA after the fusion PspA boosting. This immunization regimen effectively prevented S. pneumoniae infection.ConclusionsPrime-boost-type immunization with a fusion PspA prevented S. pneumoniae infection in mice and macaques.

Project description:BackgroundA DNA-prime/human adenovirus serotype 5 (HuAd5) boost vaccine encoding Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP) and Pf apical membrane antigen-1 (PfAMA1), elicited protection in 4/15 (27%) of subjects against controlled human malaria infection (CHMI) that was statistically associated with CD8+ T cell responses. Subjects with high level pre-existing immunity to HuAd5 were not protected, suggesting an adverse effect on vaccine efficacy (VE). We replaced HuAd5 with chimpanzee adenovirus 63 (ChAd63), and repeated the study, assessing both the two-antigen (CSP, AMA1 = CA) vaccine, and a novel three-antigen (CSP, AMA1, ME-TRAP = CAT) vaccine that included a third pre-erythrocytic stage antigen [malaria multiple epitopes (ME) fused to the Pf thrombospondin-related adhesive protein (TRAP)] to potentially enhance protection.MethodologyThis was an open label, randomized Phase 1 trial, assessing safety, tolerability, and VE against CHMI in healthy, malaria naïve adults. Forty subjects (20 each group) were to receive three monthly CA or CAT DNA priming immunizations, followed by corresponding ChAd63 boost four months later. Four weeks after the boost, immunized subjects and 12 infectivity controls underwent CHMI by mosquito bite using the Pf3D7 strain. VE was assessed by determining the differences in time to parasitemia as detected by thick blood smears up to 28-days post CHMI and utilizing the log rank test, and by calculating the risk ratio of each treatment group and subtracting from 1, with significance calculated by the Cochran-Mantel-Haenszel method.ResultsIn both groups, systemic adverse events (AEs) were significantly higher after the ChAd63 boost than DNA immunizations. Eleven of 12 infectivity controls developed parasitemia (mean 11.7 days). In the CA group, 15 of 16 (93.8%) immunized subjects developed parasitemia (mean 12.0 days). In the CAT group, 11 of 16 (63.8%) immunized subjects developed parasitemia (mean 13.0 days), indicating significant protection by log rank test compared to infectivity controls (p = 0.0406) and the CA group (p = 0.0229). VE (1 minus the risk ratio) in the CAT group was 25% compared to -2% in the CA group. The CA and CAT vaccines induced robust humoral (ELISA antibodies against CSP, AMA1 and TRAP, and IFA responses against sporozoites and Pf3D7 blood stages), and cellular responses (IFN-γ FluoroSpot responses to CSP, AMA1 and TRAP) that were not associated with protection.ConclusionsThis study demonstrated that the ChAd63 CAT vaccine exhibited significant protective efficacy, and confirmed protection was afforded by adding a third antigen (T) to a two-antigen (CA) formulation to achieve increased VE. Although the ChAd63-CAT vaccine was associated with increased frequencies of systemic AEs compared to the CA vaccine and, historically, compared to the HuAd5 vectored malaria vaccine encoding CSP and AMA1, they were transient and associated with increased vector dosing.

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A five-antigen Esx-5a fusion delivered as a prime-boost regimen protects against M.tb challenge.

Publications

A five-antigen Esx-5a fusion delivered as a prime-boost regimen protects against <i>M.tb</i> challenge.

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