Skip to main content
Springer Nature Link
Log in

Helicobacter pylori

  • Chapter
  • First Online:
Human Challenge Studies for Vaccine Development

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 445))

  • 538 Accesses

Abstract

Helicobacter pylori (H. pylori) is an important human pathogen etiologically associated with peptic ulcers and gastric cancer. The infection is present in approximately one-half of the world’s population. Population-based H. pylori eradiation has confirmed that cure or prevention of the infection produces a marked reduction in gastric cancer and peptic ulcer disease. Antimicrobial therapy has become increasingly ineffective, and complexity and costs of antimicrobial therapy for infected individuals residing in and, immigrating from, the developing world combined with the cost of treatment for cancer make vaccine development a cost-effective alternative. Challenge studies allowed making a “go–no go” decision regarding vaccine effectiveness. We provide detailed protocols regarding challenge strain selection and administration as well as guidance regarding the clinical and laboratory tests used to confirm and monitor experimental infection. Experience shows that reliance of noninvasive methods led to the erroneous conclusion that some subjects were not infected. The current data suggests that histologic assessment of gastric mucosal biopsies may be one of the most sensitive and specific means of assessment of the presence of experimental infection as well as of successful H. pylori eradication. We recommend detailed recommendations for acquiring, processing, embedding, sectioning, and examining the gastric biopsies.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Aebischer T, Bumann D, Epple HJ, Metzger W, Schneider T, Cherepnev G, Walduck AK, Kunkel D, Moos V, Loddenkemper C, Jiadze I, Panasyuk M, Stolte M, Graham DY, Zeitz M, Meyer TF (2008) Correlation of T cell response and bacterial clearance in human volunteers challenged with Helicobacter pylori revealed by randomised controlled vaccination with Ty21a-based Salmonella vaccines. Gut 57(8):1065–1072. https://doi.org/10.1136/gut.2007.145839 gut.2007.145839[pii]

    Article  PubMed  Google Scholar 

  • Atapoor S, Safarpoor DF, Rahimi E (2014) Detection of Helicobacter pylori in Various Types of Vegetables and Salads. Jundishapur J Microbiol 7(5):e10013. https://doi.org/10.5812/jjm.10013

    Article  PubMed  PubMed Central  Google Scholar 

  • Bartelloni PJ, Tesh RB (1976) Clinical and serologic responses of volunteers infected with phlebotomus fever virus (Sicilian type). Am J Trop Med Hyg 25(3):456–462

    Article  PubMed  Google Scholar 

  • Begue RE, Gonzales JL, Correa-Gracian H, Tang SC (1998) Dietary risk factors associated with the transmission of Helicobacter pylori in Lima, Peru. Am J Trop Med Hyg 59(4):637–640

    Article  PubMed  Google Scholar 

  • Black RE, Levine MM, Clements ML, Hughes TP, Blaser MJ (1988) Experimental Campylobacter jejuni infection in humans. J Infect Dis 157(3):472–479

    Article  PubMed  Google Scholar 

  • Czinn SJ, Nedrud JG (1991) Oral immunization against Helicobacter pylori. Infect Immun 59:2359–2363

    Article  PubMed  PubMed Central  Google Scholar 

  • Del Giudice G (2001) Towards the development of vaccines against Helicobacter pylori: status and issues. Curr Opin Investig Drugs 2(1):40–44

    PubMed  Google Scholar 

  • Del Giudice G, Covacci A, Telford JL, Montecucco C, Rappuoli R (2001) The design of vaccines against Helicobacter pylori and their development. Annu Rev Immunol 19:523–563

    Article  PubMed  Google Scholar 

  • Del Giudice G, Malfertheiner P, Rappuoli R (2009) Development of vaccines against Helicobacter pylori. Expert Rev Vaccines 8(8):1037–1049

    Article  PubMed  Google Scholar 

  • Dixon MF, Genta RM, Yardley JH, Correa P (1996) Classification and grading of gastritis. The updated Sydney system. International workshop on the histopathology of Gastritis, Houston 1994. Am J Surg Pathol 20:1161–1181

    Article  PubMed  Google Scholar 

  • Dunachie S, Berthoud T, Hill AVS, Fletcher HA (2015) Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model. Vaccine 33(40):5321–5331. https://doi.org/10.1016/j.vaccine.2015.07.087

    Article  PubMed  PubMed Central  Google Scholar 

  • El-Zimaity HM, Graham DY, Al-Assi MT, Malaty H, Karttunen TJ, Graham DP, Huberman RM, Genta RM (1996) Interobserver variation in the histopathological assessment of Helicobacter pylori gastritis [see comments]. Hum Pathol 27:35–41

    Article  PubMed  Google Scholar 

  • Ethical issues (2021) Human challenge studies in endemic settings: ethical and regulatory issues. SpringerBriefs in Ethnics. Springer Nature Switzerland AG

    Google Scholar 

  • Evans DG, Evans DJ Jr, Opekun AR, Graham DY (1988) Non-replicating oral whole cell vaccine protective against enterotoxigenic Escherichia coli (ETEC) diarrhea: stimulation of anti-CFA (CFA/I) and anti-enterotoxin (anti-LT) intestinal IgA and protection against challenge with ETEC belonging to heterologous serotypes. FEMS Microbiol Immunol 1(3):117–125

    Article  PubMed  Google Scholar 

  • Experimental infection in the 18th–19th century (2021). In: Jamrozik E, Selgelid MJ (eds) Human challenge studies in endemic settings: ethical and regulatory issues. SpringerBriefs in Ethics. Springer Nature Switzerland AG, pp 9–23

    Google Scholar 

  • Ford AC, Axon AT (2010) Epidemiology of Helicobacter pylori infection and public health implications. Helicobacter 15(Suppl 1):1–6. https://doi.org/10.1111/j.1523-5378.2010.00779.x

    Article  PubMed  Google Scholar 

  • Glickman JN, Noffsinger A, Nevin DT, Ray M, Lash RH, Genta RM (2015) Helicobacter infections with rare bacteria or minimal gastritis: expecting the unexpected. Dig Liver Dis 47(7):549–555. https://doi.org/10.1016/j.dld.2015.04.005

    Article  PubMed  Google Scholar 

  • Graham DY (1997) Helicobacter pylori infection in the pathogenesis of duodenal ulcer and gastric cancer: a model. Gastroenterology 113(6):1983–1991

    Article  PubMed  Google Scholar 

  • Graham DY (2014) History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World J Gastroenterol 20(18):5191–5204. https://doi.org/10.3748/wjg.v20.i18.5191[doi]

    Article  PubMed  PubMed Central  Google Scholar 

  • Graham DY (2015) Helicobacter pylori update: gastric cancer, reliable therapy, and possible benefits. Gastroenterology 148(4):719–731. https://doi.org/10.1053/j.gastro.2015.01.040 S0016-5085(15)00158-4[pii]

    Article  PubMed  Google Scholar 

  • Graham DY, El-Serag HB (2021) European registry on Helicobacter pylori management shows that gastroenterology has largely failed in its efforts to guide practitioners. Gut 70(1):1–2. https://doi.org/10.1136/gutjnl-2020-322385

    Article  PubMed  Google Scholar 

  • Graham DY, Opekun AR, Osato MS, El-Zimaity HM, Lee CK, Yamaoka Y, Qureshi WA, Cadoz M, Monath TP (2004) Challenge model for Helicobacter pylori infection in human volunteers. Gut 53(9):1235–1243

    Article  PubMed  PubMed Central  Google Scholar 

  • Hooi JKY, Lai WY, Ng WK, Suen MMY, Underwood FE, Tanyingoh D, Malfertheiner P, Graham DY, Wong VWS, Wu JCY, Chan FKL, Sung JJY, Kaplan GG, Ng SC (2017) Global prevalence of Helicobacter pylori infection: systematic review and meta-analysis. Gastroenterology 153(2):420–429. https://doi.org/10.1053/j.gastro.2017.04.022 S0016-5085(17)35531-2[pii]

    Article  PubMed  Google Scholar 

  • Hornick RB, Greisman SE, Woodward TE, DuPont HL, Dawkins AT, Snyder MJ (1970) Typhoid fever: pathogenesis and immunologic control. N Engl J Med 283(14):739–746

    Google Scholar 

  • Hu Y, Wan JH, Li XY, Zhu Y, Graham DY, Lu NH (2017) Systematic review with meta-analysis: the global recurrence rate of Helicobacter pylori. Aliment Pharmacol Ther 46(9):773–779. https://doi.org/10.1111/apt.14319[doi]

    Article  PubMed  Google Scholar 

  • Ikuse T, Blanchard TG, Czinn SJ (2019) Inflammation, immunity, and vaccine development for the gastric pathogen Helicobacter pylori. Curr Top Microbiol Immunol 421:1–19. https://doi.org/10.1007/978-3-030-15138-6_1[doi]

    Article  PubMed  Google Scholar 

  • Kennemann L, Didelot X, Aebischer T, Kuhn S, Drescher B, Droege M, Reinhardt R, Correa P, Meyer TF, Josenhans C, Falush D, Suerbaum S (2011) Helicobacter pylori genome evolution during human infection. Proc Natl Acad Sci 108(12):5033–5038. https://doi.org/10.1073/pnas.1018444108

    Article  PubMed  PubMed Central  Google Scholar 

  • Lash RH, Genta RM (2016) Routine anti-Helicobacter immunohistochemical staining is significantly superior to reflex staining protocols for the detection of Helicobacter in gastric biopsy specimens. Helicobacter 21(6):581–585. https://doi.org/10.1111/hel.12315[doi]

    Article  PubMed  Google Scholar 

  • Leja M, Grinberga-Derica I, Bilgilier C, Steininger C (2019) Review: epidemiology of Helicobacter pylori infection. Helicobacter 24(S1):e12635. https://doi.org/10.1111/hel.12635

    Article  PubMed  Google Scholar 

  • Liang W, Wang S, Yu F, Zhang L, Qi G, Liu Y, Gao S, Kan B (2003) Construction and evaluation of a safe, live, oral Vibrio cholerae vaccine candidate, IEM108. Infect Immun 71(10):5498–5504. https://doi.org/10.1128/IAI.71.10.5498-5504.2003

    Article  PubMed  PubMed Central  Google Scholar 

  • Malfertheiner P, Schultze V, Rosenkranz B, Kaufmann SH, Ulrichs T, Novicki D, Norelli F, Contorni M, Peppoloni S, Berti D, Tornese D, Ganju J, Palla E, Rappuoli R, Scharschmidt BF, Del GG (2008) Safety and immunogenicity of an intramuscular Helicobacter pylori vaccine in noninfected volunteers: a phase I study. Gastroenterology 135(3):787–795

    Article  PubMed  Google Scholar 

  • Malfertheiner P, Selgrad M, Wex T, Roessner A, Graham DY, del Giudice G (2016) 952 active gastric inflammation in human volunteers after exposure to a cag-positive H. pylori challenge in a placebo controlled vaccine Trial. Gastroenterology 150(4):S188. https://doi.org/10.1016/S0016-5085(16)30714-4

  • Malfertheiner P, Selgrad M, Wex T, Romi B, Borgogni E, Spensieri F, Zedda L, Ruggiero P, Pancotto L, Censini S, Palla E, Kanesa-Thasan N, Scharschmidt B, Rappuoli R, Graham DY, Schiavetti F, Del GG (2018) Efficacy, immunogenicity, and safety of a parenteral vaccine against Helicobacter pylori in healthy volunteers challenged with a Cag-positive strain: a randomised, placebo-controlled phase 1/2 study. Lancet Gastroenterol Hepatol 3(10):698–707. https://doi.org/10.1016/S2468-1253(18)30125-0 S2468-1253(18)30125-0[pii]

    Article  PubMed  Google Scholar 

  • Marshall BJ, Armstrong JA, McGechie DB, Glancy RJ (1985) Attempt to fulfil Koch’s postulates for pyloric Campylobacter. Med J Aust 142:436–439

    Article  PubMed  Google Scholar 

  • Miehlke S, Thomas R, Guiterrez O, Graham DY, Go MF (1999) DNA fingerprinting of single colonies of Helicobacter pylori from gastric cancer patients suggests infection with a single predominant strain. J Clin Microbiol 37(1):245–247

    Article  PubMed  PubMed Central  Google Scholar 

  • Miftahussurur M, Yamaoka Y, Graham DY (2016) Helicobacter pylori vacuolating cytotoxin and gastric cancer risk: reconsidered. Transl Cancer Res 5(Suppl 3):1–4. https://doi.org/10.21037/tcr.2016.09.33:doi

    Article  Google Scholar 

  • Miftahussurur M, Yamaoka Y, Graham DY (2017) Helicobacter pylori as an oncogenic pathogen, revisited. Expert Rev Mol Med 19:e4. https://doi.org/10.1017/erm.2017.4 S1462399417000047[pii]

    Article  PubMed  PubMed Central  Google Scholar 

  • Mills J, Van Kirk JE, Wright PF, Chanock RM (1971) Experimental respiratory syncytial virus infection of adults. Possible mechanisms of resistance to infection and illness. J Immunol 107(1):123–130

    Google Scholar 

  • Moreno Y, Ferrus MA (2012) Specific detection of cultivable Helicobacter pylori cells from wastewater treatment plants. Helicobacter 17(5):327–332. https://doi.org/10.1111/j.1523-5378.2012.00961.x[doi]

    Article  PubMed  Google Scholar 

  • Morris A, Nicholson G (1987) Ingestion of Campylobacter pyloridis causes gastritis and raised fasting gastric pH. Am J Gastroenterol 82:192–199

    PubMed  Google Scholar 

  • Morris AJ, Ali MR, Nicholson GI, Perez-Perez GI, Blaser MJ (1991) Long-term follow-up of voluntary ingestion of Helicobacter pylori. Ann Intern Med 114:662–663

    Article  PubMed  Google Scholar 

  • Nell S, Estibariz I, Krebes J, Bunk B, Graham DY, Overmann J, Song Y, Sproer C, Yang I, Wex T, Korlach J, Malfertheiner P, Suerbaum S (2017) Genome and methylome variation in Helicobacter pylori with a cag pathogenicity island during early stages of human infection. Gastroenterology. https://doi.org/10.1053/j.gastro.2017.10.014 S0016-5085(17)36273-X[pii]

    Article  PubMed  Google Scholar 

  • Nurgalieva ZZ, Conner ME, Opekun AR, Zheng CQ, Elliott SN, Ernst PB, Osato M, Estes MK, Graham DY (2005) B-cell and T-cell immune responses to experimental Helicobacter pylori infection in humans. Infect Immun 73(5):2999–3006

    Article  PubMed  PubMed Central  Google Scholar 

  • Nyssen OP, Bordin D, Tepes B, Perez-Aisa A, Vaira D, Caldas M, Bujanda L, Castro-Fernandez M, Lerang F, Leja M, Rodrigo L, Rokkas T, Kupcinskas L, Perez-Lasala J, Jonaitis L, Shvets O, Gasbarrini A, Simsek H, Axon ATR, Buzas G, Machado JC, Niv Y, Boyanova L, Goldis A, Lamy V, Tonkic A, Przytulski K, Beglinger C, Venerito M, Bytzer P, Capelle L, Milosavljevic T, Milivojevic V, Veijola L, Molina-Infante J, Vologzhanina L, Fadeenko G, Arino I, Fiorini G, Garre A, Garrido J, Puig I, Heluwaert F, Megraud F, O’Morain C, Gisbert JP, Hp-EuReg I (2021) European Registry on Helicobacter pylori management (Hp-EuReg): patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients. Gut 70(1):40–54. https://doi.org/10.1136/gutjnl-2020-321372

    Article  PubMed  Google Scholar 

  • O’Rourke JL, Lee A (2003) Animal models of Helicobacter pylori infection and disease. Microbes Infect 5(8):741–748

    Article  PubMed  Google Scholar 

  • Rossi G, Ruggiero P, Peppoloni S, Pancotto L, Fortuna D, Lauretti L, Volpini G, Mancianti S, Corazza M, Taccini E, Di PF, Rappuoli R, Del GG (2004) Therapeutic vaccination against Helicobacter pylori in the beagle dog experimental model: safety, immunogenicity, and efficacy. Infect Immun 72(6):3252–3259

    Article  PubMed  PubMed Central  Google Scholar 

  • Rugge M, Genta RM, Fassan M, Valentini E, Coati I, Guzzinati S, Savarino E, Zorzi M, Farinati F, Malfertheiner P (2018) OLGA gastritis staging for the prediction of gastric cancer risk: a long-term follow-up study of 7436 patients. Am J Gastroenterol 113(11):1621–1628. https://doi.org/10.1038/s41395-018-0353-8[doi]

    Article  PubMed  Google Scholar 

  • Sabin AB (1952) Research on dengue in World War II. Am J Trop Med Hyg 1:30–40

    Article  PubMed  Google Scholar 

  • Savoldi A, Carrara E, Graham DY, Conti M, Tacconelli E (2018) Prevalence of antibiotic resistance in Helicobacter pylori: a systematic review and meta-analysis in World Health Organization regions. Gastroenterology 155(5):1372–1382. https://doi.org/10.1053/j.gastro.2018.07.007 S0016-5085(18)34761-9[pii]

    Article  PubMed  Google Scholar 

  • Stubljar D, Jukic T, Ihan A (2018) How far are we from vaccination against Helicobacter pylori infection? Expert Rev Vaccines 17(10):935–945. https://doi.org/10.1080/14760584.2018.1526680

    Article  PubMed  Google Scholar 

  • Sutton P, Boag JM (2018) Status of vaccine research and development for Helicobacter pylori. Vaccine. https://doi.org/10.1016/j.vaccine.2018.01.001 S0264-410X(18)30017-3[pii]

    Article  PubMed  PubMed Central  Google Scholar 

  • Tacket CO, Binion SB, Bostwick E, Losonsky G, Roy MJ, Edelman R (1992) Efficacy of bovine milk immunoglobulin concentrate in preventing illness after Shigella flexneri challenge. Am J Trop Med Hyg 47(3):276–283

    Article  PubMed  Google Scholar 

  • Tan MC, Balakrishnan M, Graham DY (2018) Gastric cancer worldwide except Japan. In: Gastric cancer with special focus on studies from Japan. In: Shiotani A (ed) Gastric cancer with special focus on studies from Japan. Springer, Singapore, pp 17–28

    Google Scholar 

  • Tigertt WD, Benenson AS (1956) Studies on Q fever in man. Trans Assoc Amer Phys 60:98–104

    Google Scholar 

  • Urrutia-Baca VH, Gomez-Flores R, MA dlG-R, Tamez-Guerra P, Lucio-Sauceda DG, Rodriguez-Padilla MC (2019) Immunoinformatics approach to design a novel epitope-based oral vaccine against Helicobacter pylori. J Comput Biol. https://doi.org/10.1089/cmb.2019.0062

  • Vale FF, Vítor JMB (2010) Transmission pathway of Helicobacter pylori: does food play a role in rural and urban areas? Int J Food Microbiol 138(1):1–12. https://doi.org/10.1016/j.ijfoodmicro.2010.01.016

    Article  PubMed  Google Scholar 

  • Walduck AK, Raghavan S (2019) Immunity and vaccine development against Helicobacter pylori. Adv Exp Med Biol. https://doi.org/10.1007/5584_2019_370[doi]

    Article  PubMed  Google Scholar 

  • Yamaoka Y, Graham DY (2014) Helicobacter pylori virulence and cancer pathogenesis. Future Oncol 10(8):1487–1500. https://doi.org/10.2217/fon.14.29[doi]

    Article  PubMed  Google Scholar 

  • Zeng M, Mao XH, Li JX, Tong WD, Wang B, Zhang YJ, Guo G, Zhao ZJ, Li L, Wu DL, Lu DS, Tan ZM, Liang HY, Wu C, Li DH, Luo P, Zeng H, Zhang WJ, Zhang JY, Guo BT, Zhu FC, Zou QM (2015) Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386(10002):1457–1467. https://doi.org/10.1016/S0140-6736(15)60310-5 S0140-6736(15)60310-5[pii]

    Article  PubMed  Google Scholar 

Download references

Support

Dr. Graham is supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs, Public Health Service grant DK56338, which funds the Texas Medical Center Digestive Diseases Center.

Author information

Authors and Affiliations

  1. Department of Medicine, Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, RM 3A-390A (111D), 2002 Holcombe Boulevard, Houston, TX, 77030, USA

    David Y. Graham

Authors
  1. David Y. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Y. Graham .

Editor information

Editors and Affiliations

  1. GSK Vaccines, SIENA, Siena, Italy

    Fabio Bagnoli

  2. Siena, Italy

    Giuseppe Del Giudice

  3. GSK Vaccines, Siena, Italy

    Sanjay K. Phogat

  4. GSK Vaccines, SIENA, Siena, Italy

    Rino Rappuoli

Rights and permissions

Reprints and permissions

Copyright information

© 2021 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Graham, D.Y. (2021). Helicobacter pylori. In: Bagnoli, F., Del Giudice, G., Phogat, S.K., Rappuoli, R. (eds) Human Challenge Studies for Vaccine Development. Current Topics in Microbiology and Immunology, vol 445. Springer, Cham. https://doi.org/10.1007/82_2021_235

Download citation

Publish with us

Policies and ethics