Progress in the development of an Advax-adjuvanted protein capsular matrix vaccine against typhoid fever

Abstract

Typhoid fever, caused by Salmonella Typhi, remains a significant global public health concern, with an estimated 11 - 20 million cases annually. Vaccines are critical to controlling typhoid fever. Widespread vaccination diminishes the emergence of antibiotic-resistant strains of S. Typhi. The economic benefits of vaccination are also substantial, as the costs of treating typhoid fever and its complications can be significant. Ty21a®, a killed whole-cell vaccine, and Vivotif®, a live-attenuated vaccine, have been available for decades but have relatively short durations of action and only provide partial protection. Vi polysaccharide-conjugate vaccines have improved the durability of protection, but there is still room for improvement. Typhax™, a novel alternative to traditional conjugate vaccines, utilizes Vi polysaccharide that is non-covalently entrapped in a poly-L-lysine and CRM197 protein matrix crosslinked by glutaraldehyde. When formulated with Advax-CpG™ adjuvant, Typhax demonstrated promising results in a range of animal models including mice, rabbits, and non-human primates in which it induces high and sustained serum anti-Vi immunoglobulin G and serum bactericidal activity, without any safety or reactogenicity issues. This novel vaccine approach offers the potential for a low-cost, more effective, and durable vaccine against typhoid fever, avoiding the need for frequent booster doses.

Keywords

Vaccine / Typhoid / Adjuvant / Immunization / Advax

Funding

The writing of this paper was supported in part by the National Institutes of Health, National Institute of Allergy and Infectious Diseases, USA (grand no.: HHSN272200800039C, HHSN272201400053C, and HHSN272201800044C). The paper’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health, National Institute of Allergy and Infectious Diseases.

Conflict of interest

Nikolai Petrovsky is an affiliate of Vaxine Pty Ltd which has proprietary interests in Advax-CpG adjuvant, while Kevin P. Killeen is an affiliate of Matrivax Inc. which has proprietary interests in the Typhax vaccine.

References

[1] Khan MI, Soofi SB, Ochiai RL, et al. Epidemiology, clinical presentation, and patterns of drug resistance of Salmonella Typhi in Karachi, Pakistan. J Infect Dev Ctries. 2012; 6:704-14. doi: 10.3855/jidc.1967

[2] Typhoid GBD, Paratyphoid C. The global burden of typhoid and paratyphoid fevers: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Infect Dis. 2019;19:369-381. doi: 10.1016/S1473-3099(18)30685-6

[3] Mohsen Y, Tarchichi N, Barakat R, et al. The different types of metallophores produced by Salmonella enterica: A review. Microbiol Res. 2023;14:1457-1469.

[4] Karkey A, Thwaites GE, Baker S. The evolution of antimicrobial resistance in Salmonella Typhi. Curr Opin Gastroenterol. 2018; 34:25-30. doi: 10.1097/MOG.0000000000000406

[5] Levine MM. Use of vaccines for the prevention of typhoid fever. Indian Pediatr. 2003;40:1029-1034.

[6] Sarma VN, Malaviya AN, Kumar R, Ghai OP, Bakhtary MM. Development of immune response during typhoid fever in man. Clin Exp Immunol. 1977;28:35-39.

[7] Levine MM, Ferreccio C, Abrego P, Martin OS, Ortiz E, Cryz S. Duration of efficacy of Ty21a, attenuated Salmonella typhi live oral vaccine. Vaccine. 1999;17Suppl 2:S22-S27. doi: 10.1016/s0264-410x(99)00231-5

[8] Darton TC, Jones C, Blohmke CJ, et al. Using a human challenge model of infection to measure vaccine efficacy: A randomised, controlled trial comparing the typhoid vaccines M01ZH09 with Placebo and Ty21a. PLoS Negl Trop Dis. 2016;10:e0004926. doi: 10.1371/journal.pntd.0004926

[9] Sur D, Ochiai RL, Bhattacharya SK, et al. A cluster-randomized effectiveness trial of Vi typhoid vaccine in India. N Engl J Med. 2009;361:335-344. doi: 10.1056/NEJMoa0807521

[10] Khan MI, Soofi SB, Ochiai RL, et al. Effectiveness of Vi capsular polysaccharide typhoid vaccine among children: A cluster randomized trial in Karachi, Pakistan. Vaccine. 2012; 30:5389-5395. doi: 10.1016/j.vaccine.2012.06.015

[11] Anwar E, Goldberg E, Fraser A, Acosta CJ, Paul M, Leibovici L.Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. 2014;2014:CD001261. doi: 10.1002/14651858.CD001261.pub3

[12] Milligan R, Paul M, Richardson M, Neuberger A.Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. 2018;5:CD001261. doi: 10.1002/14651858.CD001261.pub4

[13] Mohan VK, Varanasi V, Singh A, et al. Safety and immunogenicity of a Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar-TCV) in healthy infants, children, and adults in typhoid endemic areas: A multicenter, 2-cohort, open-label, double-blind, randomized controlled phase 3 study. Clin Infect Dis. 2015;61:393-402. doi: 10.1093/cid/civ295

[14] Capeding MR, Alberto E, Sil A, et al. Immunogenicity, safety and reactogenicity of a Phase II trial of Vi-DT typhoid conjugate vaccine in healthy Filipino infants and toddlers: A preliminary report. Vaccine. 2020; 38:4476-4483. doi: 10.1016/J.VACCINE.2019.09.074

[15] Mai NL, Phan VB, Vo AH, et al. Persistent efficacy of Vi conjugate vaccine against typhoid fever in young children. N Engl J Med. 2003;349:1390-1391. doi: 10.1056/NEJM200310023491423

[16] Capeding MR, Teshome S, Saluja T, et al. Safety and immunogenicity of a Vi-DT typhoid conjugate vaccine: Phase I trial in Healthy Filipino adults and children. Vaccine. 2018; 36:3794-3801. doi: 10.1016/j.vaccine.2018.05.038

[17] An SJ, Yoon YK, Kothari S, et al. Immune suppression induced by Vi capsular polysaccharide is overcome by Vi-DT conjugate vaccine. Vaccine. 2012; 30:1023-1028. doi: 10.1016/j.vaccine.2011.12.046

[18] Zuckerman JN, Hatz C, Kantele A. Review of current typhoid fever vaccines, cross-protection against paratyphoid fever, and the European guidelines. Expert Rev Vaccines. 2017;16:1029-1043. doi: 10.1080/14760584.2017.1374861

[19] Griffin TJ 4^th, Thanawastien A, Cartee RT, Mekalanos JJ, Killeen KP. In vitro characterization and preclinical immunogenicity of Typhax, a typhoid fever protein capsular matrix vaccine candidate. Hum Vaccin Immunother. 2019;15:1310-1316. doi: 10.1080/21645515.2019.1599674

[20] Juel HB, Thomaides-Brears HB, Darton TC, et al. Salmonella Typhi bactericidal antibodies reduce disease severity but do not protect against typhoid fever in a controlled human infection model. Front Immunol. 2017; 8:1916. doi: 10.3389/fimmu.2017.01916

[21] Petrovsky N, Aguilar JC. Vaccine adjuvants: Current state and future trends. Immunol Cell Biol. 2004; 82:488-496. doi: 10.1111/j.0818-9641.2004.01272.x

[22] Stewart EL, Counoupas C, Johansen MD, et al.Mucosal immunization with a delta-inulin adjuvanted recombinant spike vaccine elicits lung-resident immune memory and protects mice against SARS-CoV-2. Mucosal Immunol. 2022;15:1405-1415. doi: 10.1038/s41385-022-00578-9

[23] Xu S, Yang K, Li R, Zhang L.mRNA vaccine era-mechanisms, drug platform and clinical prospection. Int J Mol Sci. 2020;21:6582. doi: 10.3390/ijms21186582

[24] Honda-Okubo Y, Cartee RT, Thanawastien A, Seung Yang J, Killeen KP, Petrovsky N. A typhoid fever protein capsular matrix vaccine candidate formulated with Advax- CpG adjuvant induces a robust and durable anti-typhoid Vi polysaccharide antibody response in mice, rabbits and nonhuman primates. Vaccine. 2022; 40:4625-4634. doi: 10.1016/j.vaccine.2022.06.043

[25] Cartee RT, Thanawastien A, Griffin Iv TJ, Mekalanos JJ, Bart S, Killeen KP. A phase 1 randomized safety, reactogenicity, and immunogenicity study of Typhax: A novel protein capsular matrix vaccine candidate for the prevention of typhoid fever. PLoS Negl Trop Dis. 2020;14:e0007912. doi: 10.1371/journal.pntd.0007912

[26] Katkocin DM. Characterization of multivalent pneumococcal conjugate vaccines. Dev Biol (Basel). 2000;103:113-119.

[27] Singleton KL, Joffe A, Leitner WW. Review: Current trends, challenges, and success stories in adjuvant research. Front Immunol. 2023;14:1105655. doi: 10.3389/fimmu.2023.1105655

[28] Cooper PD, Barclay TG, Ginic-Markovic M, Petrovsky N. The polysaccharide inulin is characterized by an extensive series of periodic isoforms with varying biological actions. Glycobiology. 2013;23:1164-1174. doi: 10.1093/glycob/cwt053

[29] Cooper PD, Petrovsky N. Delta inulin: A novel, immunologically active, stable packing structure comprising beta-D-[2 -> 1] poly(fructo-furanosyl) alpha-D-glucose polymers. Glycobiology. 2011;21:595-606. doi: 10.1093/glycob/cwq201

[30] Petrovsky N, Cooper PD. Advax, a novel microcrystalline polysaccharide particle engineered from delta inulin, provides robust adjuvant potency together with tolerability and safety. Vaccine. 2015; 33:5920-5926. doi: 10.1016/j.vaccine.2015.09.030

[31] Counoupas C, Pinto R, Nagalingam G, Britton WJ, Petrovsky N, Triccas JA. Delta inulin-based adjuvants promote the generation of polyfunctional CD4(+) T cell responses and protection against Mycobacterium tuberculosis infection. Sci Rep. 2017;7:8582. doi: 10.1038/s41598-017-09119-y

[32] Honda-Okubo Y, Barnard D, Ong CH, Peng BH, Tseng CT, Petrovsky N. Severe acute respiratory syndrome-associated coronavirus vaccines formulated with delta inulin adjuvants provide enhanced protection while ameliorating lung eosinophilic immunopathology. J Virol. 2015; 89:2995-3007. doi: 10.1128/JVI.02980-14

[33] Honda-Okubo Y, Saade F, Petrovsky N. Advax, a polysaccharide adjuvant derived from delta inulin, provides improved influenza vaccine protection through broad-based enhancement of adaptive immune responses. Vaccine. 2012; 30:5373-5381. doi: 10.1016/j.vaccine.2012.06.021

[34] Larena M, Prow NA, Hall RA, Petrovsky N, Lobigs M. JE-ADVAX vaccine protection against Japanese encephalitis virus mediated by memory B cells in the absence of CD8(+) T cells and pre-exposure neutralizing antibody. J Virol. 2013; 87:4395-4402. doi: 10.1128/JVI.03144-12

[35] Li L, Honda-Okubo Y, Li C, Sajkov D, Petrovsky N. Delta inulin adjuvant enhances plasmablast generation, expression of activation-induced cytidine deaminase and B-cell affinity maturation in human subjects receiving seasonal influenza vaccine. PLoS One. 2015;10:e0132003. doi: 10.1371/journal.pone.0132003

[36] Petrovsky N, Larena M, Siddharthan V, et al. An inactivated cell culture Japanese encephalitis vaccine (JE-ADVAX) formulated with delta inulin adjuvant provides robust heterologous protection against West Nile encephalitis via cross-protective memory B cells and neutralizing antibody. J Virol. 2013; 87:10324-10333. doi: 10.1128/JVI.00480-13

[37] Davtyan H, Zagorski K, Rajapaksha H, et al. Alzheimer’s disease Advax(CpG)-adjuvanted MultiTEP-based dual and single vaccines induce high-titer antibodies against various forms of tau and Abeta pathological molecules. Sci Rep. 2016;6:28912. doi: 10.1038/srep28912

[38] Gordon D, Kelley P, Heinzel S, Cooper P, Petrovsky N. Immunogenicity and safety of Advax, a novel polysaccharide adjuvant based on delta inulin, when formulated with hepatitis B surface antigen: A randomized controlled Phase 1 study. Vaccine. 2014; 32:6469-6477. doi: 10.1016/j.vaccine.2014.09.034

[39] Gordon DL, Sajkov D, Honda-Okubo Y, et al. Human Phase 1 trial of low-dose inactivated seasonal influenza vaccine formulated with Advax delta inulin adjuvant. Vaccine. 2016; 34:3780-3786. doi: 10.1016/j.vaccine.2016.05.071

[40] Heddle R, Smith A, Woodman R, Hissaria P, Petrovsky N. Randomized controlled trial demonstrating the benefits of delta inulin adjuvanted immunotherapy in patients with bee venom allergy. J Allergy Clin Immunol. 2019; 144:504-513. e16. doi: 10.1016/j.jaci.2019.03.035

[41] Li L, Honda-Okubo Y, Baldwin J, Bowen R, Bielefeldt-Ohmann H, Petrovsky N. Covax-19/Spikogen(R) vaccine based on recombinant spike protein extracellular domain with Advax-CpG55.2 adjuvant provides single dose protection against SARS-CoV-2 infection in hamsters. Vaccine. 2022; 40:3182-3192. doi: 10.1016/j.vaccine.2022.04.041

[42] Tabarsi P, Anjidani N, Shahpari R, et al.Evaluating the efficacy and safety of SpikoGen(R), an Advax-CpG55.2- adjuvanted severe acute respiratory syndrome coronavirus 2 spike protein vaccine: A phase 3 randomized placebo-controlled trial. Clin Microbiol Infect. 2023; 29:215-220. doi: 10.1016/j.cmi.2022.09.001

[43] Tabarsi P, Anjidani N, Shahpari R, et al.Safety and immunogenicity of SpikoGen(R), an Advax-CpG55.2-adjuvanted SARS-CoV-2 spike protein vaccine: A phase 2 randomized placebo-controlled trial in both seropositive and seronegative populations. Clin Microbiol Infect. 2022; 28:1263-1271. doi: 10.1016/j.cmi.2022.04.004

[44] Tabarsi P, Anjidani N, Shahpari R, et al. Immunogenicity and safety of SpikoGen(R), an adjuvanted recombinant SARS-CoV-2 spike protein vaccine as a homologous and heterologous booster vaccination: A randomized placebo-controlled trial. Immunology. 2022; 167:340-353. doi: 10.1111/imm.13540

[45] Sakala IG, Eichinger KM, Petrovsky N. Neonatal vaccine effectiveness and the role of adjuvants. Expert Rev Clin Immunol. 2019; 15:869-878. doi: 10.1080/1744666X.2019.1642748

[46] Honda-Okubo Y, Ong CH, Petrovsky N. Advax delta inulin adjuvant overcomes immune immaturity in neonatal mice thereby allowing single-dose influenza vaccine protection. Vaccine. 2015; 33:4892-4900. doi: 10.1016/j.vaccine.2015.07.051

[47] Sakala IG, Honda-Okubo Y, Li L, Baldwin J, Petrovsky N. A M2 protein-based universal influenza vaccine containing Advax-SM adjuvant provides newborn protection via maternal or neonatal immunization. Vaccine. 2021; 39:5162-5172. doi: 10.1016/j.vaccine.2021.07.037

[48] Poolman J, Borrow R. Hyporesponsiveness and its clinical implications after vaccination with polysaccharide or glycoconjugate vaccines. Expert Rev Vaccines. 2011; 10:307-322. doi: 10.1586/erv.11.8

[49] Keitel WA, Bond NL, Zahradnik JM, Cramton TA, Robbins JB. Clinical and serological responses following primary and booster immunization with Salmonella typhi Vi capsular polysaccharide vaccines. Vaccine. 1994;12:195-199. doi: 10.1016/0264-410x(94)90194-5

[50] Yang JS, Kim HJ, Yun CH, et al. A semi-automated vibriocidal assay for improved measurement of cholera vaccine-induced immune responses. J Microbiol Methods. 2007; 71:141-146. doi: 10.1016/j.mimet.2007.08.009

[51] Maslanka SE, Gheesling LL, Libutti DE, et al. Standardization and a multilaboratory comparison of Neisseria meningitidis serogroup A and C serum bactericidal assays. The Multilaboratory Study Group. Clin Diagn Lab Immunol. 1997; 4:156-167. doi: 10.1128/cdli.4.2.156-167.1997

[52] Pulickal AS, Gautam S, Clutterbuck EA, et al. Kinetics of the natural, humoral immune response to Salmonella enterica serovar Typhi in Kathmandu, Nepal. Clin Vaccine Immunol. 2009; 16:1413-1419. doi: 10.1128/CVI.00245-09

[53] Feasey NA, Levine MM. Typhoid vaccine development with a human challenge model. Lancet. 2017;390:2419-2421. doi: 10.1016/S0140-6736(17)32407-8

[54] Waddington CS, Darton TC, Woodward WE, Angus B, Levine MM, Pollard AJ. Advancing the management and control of typhoid fever: A review of the historical role of human challenge studies. J Infect. 2014; 68:405-418. doi: 10.1016/j.jinf.2014.01.006