Development of a Shigella Conjugate Vaccine Targeting Shigella Flexneri 6 That is Immunogenic and Provides Protection Against Virulent Challenge

Overview

Journal Vaccine

Specialty Allergy & Immunology

Date 2024 Sep 1

PMID 39217775

Authors

Meagan Kelly

Jeshina Janardhanan

Chanchal Wagh

Smriti Verma

Richelle C Charles

Daniel T Leung

Mohammad Kamruzzaman

Ruchir Kumar Pansuriya

Fahima Chowdhury

Willie F Vann

Robert W Kaminski

Ashraful Islam Khan

Taufiqur Rahman Bhuiyan

Firdausi Qadri

Pavol Kovac

Peng Xu

Edward T Ryan

Affiliations

Soon will be listed here.

Abstract

Immunity protective against shigella infection targets the bacterial O-specific polysaccharide (OSP) component of lipopolysaccharide. A multivalent shigella vaccine would ideally target the most common global Shigella species and serotypes such as Shigella flexneri 2a, S. flexneri 3a, S. flexneri 6, and S. sonnei. We previously reported development of shigella conjugate vaccines (SCVs) targeting S. flexneri 2a (SCV-Sf2a) and 3a (SCV-Sf3a) using a platform squaric acid chemistry conjugation approach and carrier protein rTTHc, a 52 kDa recombinant protein fragment of the heavy chain of tetanus toxoid. Here we report development of a SCV targeting S. flexneri 6 (SCV-Sf6) using the same platform approach. We demonstrated that SCV-Sf6 was recognized by serotype-specific monoclonal antibodies and convalescent sera of humans recovering from shigellosis in Bangladesh, suggesting correct immunological display of OSP. We vaccinated mice and found induction of serotype-specific OSP and LPS IgG and IgM responses, as well as rTTHc-specific IgG responses. Immune responses were increased when administered with aluminum phosphate adjuvant. Vaccination induced bactericidal antibody responses against S. flexneri 6, and vaccinated animals were protected against lethal challenge with virulent S. flexneri 6. Our results assist in the development of a multivalent vaccine protective against shigellosis.

References

Kotloff K . The Burden and Etiology of Diarrheal Illness in Developing Countries. Pediatr Clin North Am. 2017; 64(4):799-814. DOI: 10.1016/j.pcl.2017.03.006. View

Cohen D, Green M, Block C, Slepon R, Ofek I . Prospective study of the association between serum antibodies to lipopolysaccharide O antigen and the attack rate of shigellosis. J Clin Microbiol. 1991; 29(2):386-9. PMC: 269772. DOI: 10.1128/jcm.29.2.386-389.1991. View

Pitisuttithum P, Islam D, Chamnanchanunt S, Ruamsap N, Khantapura P, Kaewkungwal J . Clinical Trial of an Oral Live Shigella sonnei Vaccine Candidate, WRSS1, in Thai Adults. Clin Vaccine Immunol. 2016; 23(7):564-75. PMC: 4933782. DOI: 10.1128/CVI.00665-15. View

Hatz C, Bally B, Rohrer S, Steffen R, Kramme S, Siegrist C . Safety and immunogenicity of a candidate bioconjugate vaccine against Shigella dysenteriae type 1 administered to healthy adults: A single blind, partially randomized Phase I study. Vaccine. 2015; 33(36):4594-601. DOI: 10.1016/j.vaccine.2015.06.102. View

Odundo E, Weerts H, Musila L, Ogonda L, Dreyer A, Schneider J . Immunization of Rabbits with a Quadrivalent Bioconjugate Vaccine Induces Functional Antibodies Reactive with Isolates from Kenya. mSphere. 2022; 7(3):e0102021. PMC: 9241535. DOI: 10.1128/msphere.01020-21. View

van der Put R, Smitsman C, de Haan A, Hamzink M, Timmermans H, Uittenbogaard J . The First-in-Human Synthetic Glycan-Based Conjugate Vaccine Candidate against . ACS Cent Sci. 2022; 8(4):449-460. PMC: 9088300. DOI: 10.1021/acscentsci.1c01479. View

Raqib R, Venkatesan M . Shigella conjugate vaccine efficacy trial in controlled human model and potential immune correlates of protection. EBioMedicine. 2021; 66:103343. PMC: 8082079. DOI: 10.1016/j.ebiom.2021.103343. View

Riddle M, Kaminski R, Di Paolo C, Porter C, Gutierrez R, Clarkson K . Safety and Immunogenicity of a Candidate Bioconjugate Vaccine against Shigella flexneri 2a Administered to Healthy Adults: a Single-Blind, Randomized Phase I Study. Clin Vaccine Immunol. 2016; 23(12):908-917. PMC: 5139601. DOI: 10.1128/CVI.00224-16. View

Cohen D, Ashkenazi S, Green M, Gdalevich M, ROBIN G, Slepon R . Double-blind vaccine-controlled randomised efficacy trial of an investigational Shigella sonnei conjugate vaccine in young adults. Lancet. 1997; 349(9046):155-9. DOI: 10.1016/S0140-6736(96)06255-1. View

10.

Cohen D, Bassal R, Goren S, Rouach T, Taran D, Schemberg B . Recent trends in the epidemiology of shigellosis in Israel. Epidemiol Infect. 2014; 142(12):2583-94. PMC: 9151250. DOI: 10.1017/S0950268814000260. View

11.

Akter A, Kelly M, Charles R, Harris J, Calderwood S, Bhuiyan T . Parenteral Vaccination with a Cholera Conjugate Vaccine Boosts Vibriocidal and Anti-OSP Responses in Mice Previously Immunized with an Oral Cholera Vaccine. Am J Trop Med Hyg. 2021; 104(6):2024-2030. PMC: 8176512. DOI: 10.4269/ajtmh.20-1511. View

12.

Kotloff K, Winickoff J, Ivanoff B, Clemens J, Swerdlow D, Sansonetti P . Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Bull World Health Organ. 1999; 77(8):651-66. PMC: 2557719. View

13.

Jeon S, Kelly M, Yun J, Lee B, Park M, Whang Y . Scalable production and immunogenicity of a cholera conjugate vaccine. Vaccine. 2021; 39(47):6936-6946. PMC: 8609181. DOI: 10.1016/j.vaccine.2021.10.005. View

14.

Turbyfill K, Hartman A, Oaks E . Isolation and characterization of a Shigella flexneri invasin complex subunit vaccine. Infect Immun. 2000; 68(12):6624-32. PMC: 97759. DOI: 10.1128/IAI.68.12.6624-6632.2000. View

15.

Rahman K, El Arifeen S, Zaman K, Rahman M, Raqib R, Yunus M . Safety, dose, immunogenicity, and transmissibility of an oral live attenuated Shigella flexneri 2a vaccine candidate (SC602) among healthy adults and school children in Matlab, Bangladesh. Vaccine. 2010; 29(6):1347-54. DOI: 10.1016/j.vaccine.2010.10.035. View

16.

Levine M, Kotloff K, Barry E, Pasetti M, Sztein M . Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road. Nat Rev Microbiol. 2007; 5(7):540-53. PMC: 3771495. DOI: 10.1038/nrmicro1662. View

17.

Frenck Jr R, Baqar S, Alexander W, Dickey M, McNeal M, El-Khorazaty J . A Phase I trial to evaluate the safety and immunogenicity of WRSs2 and WRSs3; two live oral candidate vaccines against Shigella sonnei. Vaccine. 2018; 36(32 Pt B):4880-4889. PMC: 10559265. DOI: 10.1016/j.vaccine.2018.06.063. View

18.

Kaminski R, Wu M, Turbyfill K, Clarkson K, Tai B, Bourgeois A . Development and preclinical evaluation of a trivalent, formalin-inactivated Shigella whole-cell vaccine. Clin Vaccine Immunol. 2014; 21(3):366-82. PMC: 3957668. DOI: 10.1128/CVI.00683-13. View

19.

Mo Y, Fang W, Li H, Chen J, Hu X, Wang B . Safety and Immunogenicity of a Bivalent Conjugate Vaccine (ZF0901) in 3-Month- to 5-Year-Old Children in China. Vaccines (Basel). 2022; 10(1). PMC: 8780113. DOI: 10.3390/vaccines10010033. View

20.

Livio S, Strockbine N, Panchalingam S, Tennant S, Barry E, Marohn M . Shigella isolates from the global enteric multicenter study inform vaccine development. Clin Infect Dis. 2014; 59(7):933-41. PMC: 4166982. DOI: 10.1093/cid/ciu468. View