A Protective, Single-visit TB Vaccination Regimen by Co-administration of a Subunit Vaccine with BCG

Overview

Journal NPJ Vaccines

Date 2023 May 10

PMID 37160970

Authors

Karin Dijkman

Thomas Lindenstrom

Ida Rosenkrands

Rikke Soe

Joshua S Woodworth

Cecilia S Lindestam Arlehamn

Rasmus Mortensen

Affiliations

Soon will be listed here.

Abstract

The only licensed tuberculosis (TB) vaccine, Bacillus Calmette Guerin (BCG), fails to reliably protect adolescents and adults from pulmonary TB, resulting in ~1.6 million deaths annually. Protein subunit vaccines have shown promise against TB in clinical studies. Unfortunately, most subunit vaccines require multiple administrations, which increases the risk of loss to follow-up and necessitates more complex and costly logistics. Given the well-documented adjuvant effect of BCG, we hypothesized that BCG co-administration could compensate for a reduced number of subunit vaccinations. To explore this, we developed an expression-optimized version of our H107 vaccine candidate (H107e), which does not cross-react with BCG. In the CAF®01 adjuvant, a single dose of H107e induced inferior protection compared to three H107e/CAF®01 administrations. However, co-administering a single dose of H107e/CAF®01 with BCG significantly improved protection, which was equal to BCG co-administered with three H107e/CAF®01 doses. Importantly, combining BCG with a single H107e/CAF®01 dose also increased protection in previously BCG-primed animals. Overall, a single dose of H107e/CAF®01 with BCG induced long-lived immunity and triggered BCG-specific Th17 responses. These data support co-administration of BCG and subunit vaccines in both BCG naïve and BCG-primed individuals as an improved TB vaccine strategy with reduced number of vaccination visits.

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References

Barouch D, Stephenson K, Sadoff J, Yu J, Chang A, Gebre M . Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination. N Engl J Med. 2021; 385(10):951-953. PMC: 8314733. DOI: 10.1056/NEJMc2108829. View

Arlehamn C, McKinney D, Carpenter C, Paul S, Rozot V, Makgotlho E . A Quantitative Analysis of Complexity of Human Pathogen-Specific CD4 T Cell Responses in Healthy M. tuberculosis Infected South Africans. PLoS Pathog. 2016; 12(7):e1005760. PMC: 4943605. DOI: 10.1371/journal.ppat.1005760. View

van Haren S, Pedersen G, Kumar A, Ruckwardt T, Moin S, Moore I . CAF08 adjuvant enables single dose protection against respiratory syncytial virus infection in murine newborns. Nat Commun. 2022; 13(1):4234. PMC: 9346114. DOI: 10.1038/s41467-022-31709-2. View

Henriksen-Lacey M, Bramwell V, Christensen D, Agger E, Andersen P, Perrie Y . Liposomes based on dimethyldioctadecylammonium promote a depot effect and enhance immunogenicity of soluble antigen. J Control Release. 2009; 142(2):180-6. DOI: 10.1016/j.jconrel.2009.10.022. View

Enriquez A, Sia J, Dkhar H, Goh S, Quezada M, Stallings K . impedes CD40-dependent notch signaling to restrict Th polarization during infection. iScience. 2022; 25(5):104305. PMC: 9108765. DOI: 10.1016/j.isci.2022.104305. View

Baisley K, Kemp T, Kreimer A, Basu P, Changalucha J, Hildesheim A . Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose of HPV vaccine in historical cohorts: an immunobridging analysis of a randomised controlled trial. Lancet Glob Health. 2022; 10(10):e1485-e1493. PMC: 9638025. DOI: 10.1016/S2214-109X(22)00306-0. View

Tian S, Chen H, Sun T, Wang H, Zhang X, Liu Y . Expression, purification and characterization of Esx-1 secretion-associated protein EspL from Mycobacterium tuberculosis. Protein Expr Purif. 2016; 128:42-51. DOI: 10.1016/j.pep.2016.08.001. View

Woodworth J, Clemmensen H, Battey H, Dijkman K, Lindenstrom T, Salvador Laureano R . A Mycobacterium tuberculosis-specific subunit vaccine that provides synergistic immunity upon co-administration with Bacillus Calmette-Guérin. Nat Commun. 2021; 12(1):6658. PMC: 8602668. DOI: 10.1038/s41467-021-26934-0. View

La Torre G, Saulle R, Unim B, Meggiolaro A, Barbato A, Mannocci A . The effectiveness of measles-mumps-rubella (MMR) vaccination in the prevention of pediatric hospitalizations for targeted and untargeted infections: A retrospective cohort study. Hum Vaccin Immunother. 2017; 13(8):1879-1883. PMC: 5557224. DOI: 10.1080/21645515.2017.1330733. View

10.

Clemmensen H, Knudsen N, Billeskov R, Rosenkrands I, Jungersen G, Aagaard C . Rescuing ESAT-6 Specific CD4 T Cells From Terminal Differentiation Is Critical for Long-Term Control of Murine Mtb Infection. Front Immunol. 2020; 11:585359. PMC: 7677256. DOI: 10.3389/fimmu.2020.585359. View

11.

Kaura A, Trickey A, Shah A, Benedetto U, Glampson B, Mulla A . Comparing the longer-term effectiveness of a single dose of the Pfizer-BioNTech and Oxford-AstraZeneca COVID-19 vaccines across the age spectrum. EClinicalMedicine. 2022; 46:101344. PMC: 8918854. DOI: 10.1016/j.eclinm.2022.101344. View

12.

Di Pietrantonj C, Rivetti A, Marchione P, Debalini M, Demicheli V . Vaccines for measles, mumps, rubella, and varicella in children. Cochrane Database Syst Rev. 2021; 11:CD004407. PMC: 8607336. DOI: 10.1002/14651858.CD004407.pub5. View

13.

Dietrich J, Billeskov R, Doherty T, Andersen P . Synergistic effect of bacillus calmette guerin and a tuberculosis subunit vaccine in cationic liposomes: increased immunogenicity and protection. J Immunol. 2007; 178(6):3721-30. DOI: 10.4049/jimmunol.178.6.3721. View

14.

Leentjens J, Kox M, Stokman R, Gerretsen J, Diavatopoulos D, van Crevel R . BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J Infect Dis. 2015; 212(12):1930-8. DOI: 10.1093/infdis/jiv332. View

15.

Greenbaum J, Sidney J, Chung J, Brander C, Peters B, Sette A . Functional classification of class II human leukocyte antigen (HLA) molecules reveals seven different supertypes and a surprising degree of repertoire sharing across supertypes. Immunogenetics. 2011; 63(6):325-35. PMC: 3626422. DOI: 10.1007/s00251-011-0513-0. View

16.

Counoupas C, Johansen M, Stella A, Nguyen D, Ferguson A, Aggarwal A . A single dose, BCG-adjuvanted COVID-19 vaccine provides sterilising immunity against SARS-CoV-2 infection. NPJ Vaccines. 2021; 6(1):143. PMC: 8633321. DOI: 10.1038/s41541-021-00406-4. View

17.

Weng C, Chong L, Jia X, Zheng R, Huang Y, Zhu T . Anti-Dll4 Antibody Inhibits the Differentiation of Th17 Cells in Asthmatic Mice. Inflammation. 2017; 40(6):1975-1982. DOI: 10.1007/s10753-017-0638-x. View

18.

Schick J, Altunay M, Lacorcia M, Marschner N, Westermann S, Schluckebier J . IL-4 and helminth infection downregulate MINCLE-dependent macrophage response to mycobacteria and Th17 adjuvanticity. Elife. 2023; 12. PMC: 9908076. DOI: 10.7554/eLife.72923. View

19.

Agger E, Rosenkrands I, Hansen J, Brahimi K, Vandahl B, Aagaard C . Cationic liposomes formulated with synthetic mycobacterial cordfactor (CAF01): a versatile adjuvant for vaccines with different immunological requirements. PLoS One. 2008; 3(9):e3116. PMC: 2525815. DOI: 10.1371/journal.pone.0003116. View

20.

Dijkman K, Aguilo N, Boot C, Hofman S, Sombroek C, Vervenne R . Pulmonary MTBVAC vaccination induces immune signatures previously correlated with prevention of tuberculosis infection. Cell Rep Med. 2021; 2(1):100187. PMC: 7817873. DOI: 10.1016/j.xcrm.2020.100187. View