Comment
At last, vaccine-induced protection against Helicobacter pylori establishment of H pylori infection or eradicates at some time after colonisation is unknown); third, assess protection by measurement of subsequent acquisition of natural infection (rather than therapeutic vaccination or use of a challenge strain);4,6 fourth, use a fusion protein that might increase the efficiency of uptake and delivery of the vaccine antigen; and finally, vaccinate children. The age of the population in the present study is potentially important. H pylori transmission typically happens during childhood and new infections in adults are uncommon. The reason for this point is unknown, but might relate to a key transmission route to children from parents,7,8 or to physiological differences between children and adults that affect H pylori infectivity. Whatever the reason, a vaccine intended to prevent H pylori infection is perhaps more likely to reveal efficacy when tested in children, who are the main host initially colonised by these bacteria, than in adults. The most important achievement of Zeng and colleagues’ study5 might be to provide the first demonstration that vaccination can prevent H pylori infection in humans. However, whether an oral urease B subunit LTB vaccine will become a vaccine for widespread use against H pylori remains to be seen, in view of the challenges that still remain. First, vaccine recipients fasted for 2 h and were given a bicarbonate solution (presumably to buffer stomach acid and prevent vaccine degradation) before vaccination. Such an approach is unlikely to be feasible
www.thelancet.com Published online July 1, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60579-7
Published Online July 1, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60579-7 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)60310-5
Science Photo Library
For a quarter of a century, countless attempts have been made to produce an effective vaccine against Helicobacter pylori, a major cause of peptic ulcer disease and gastric adenocarcinoma.1 An effective vaccine against H pylori is needed most for prevention of gastric adenocarcinoma, the third leading cause of cancer-related death worldwide.2 However, efforts to produce such a vaccine have so far failed, and H pylori vaccine research has slowed in the past few years. The main reason for this might have been disillusionment, arising from the inability to produce a vaccine that completely protects against the infection.3 Vaccine trials in mice have typically achieved only small reductions in the numbers of colonising H pylori. The story is similar in clinical trials, with only one showing potential efficacy, a small reduction in colonisation after therapeutic vaccination of infected volunteers.4 Hence, Ming Zeng and colleagues’ publication5 in The Lancet, of a randomised, double-blinded, placebo-controlled, phase 3 vaccine trial that shows a significant reduction in acquisition of natural H pylori infection, is a major advance. Zeng and colleagues orally vaccinated H pyloriuninfected children (aged 6–15 years) in China with three doses of a fusion protein composed of the B subunits of H pylori urease and heat-labile toxin (LTB) of Escherichia coli. After 1 year, 14 infections were recorded in 2199 children given the H pylori vaccine, compared with 50 infections in 2204 who received placebo, resulting in a vaccine efficacy of 71·8% (95% CI 48·2–85·6).5 Some study participants were followed up in a trial extension for an additional 2 years. Although H pylori acquisition continued to be lower in vaccinated than unvaccinated children, protection levels were less than in the first year (55% fewer new infections in vaccinated vs placebo), suggesting a possible waning of protection. That this urease B subunit-containing vaccine induced protection is intriguing, because previous vaccine trials, including some which contained H pylori urease (which includes the urease B subunit), were less successful.4,6 So what was different about this latest trial? Zeng and colleagues’ study5 is the first H pylori human vaccine trial to: first, reach phase 3 and thus immunise a large cohort; second, follow vaccine recipients over years, rather than months (whether vaccine-induced protection prevents
1
Comment
for a globally marketed vaccine, suggesting more formulation work and testing will be needed; the effects that modification of this protocol will have on vaccine efficacy also need to be established. Second, the use of LTB, which binds GM1 gangliosides, might raise regulatory eyebrows. When delivered nasally, the ganglioside-binding property of LTB can result in retrograde axonal transport, possibly to the facial nerve, such that even detoxified adjuvant is capable of causing Bell’s palsy.9 This very rare side-effect was responsible for withdrawal of an initially approved and released, nasally delivered influenza vaccine.9 Although oral delivery might help avoid such issues, these well documented side-effects are likely to attract scrutiny from regulatory authorities for any mucosal-delivered vaccine containing LTB. Third, there is an issue around the level of protection, which seems to wane after 1 year. In view of the high degree of morbidity and mortality associated with H pylori-associated gastric cancer, a vaccine that protects more than 70% of recipients from infection would be of enormous benefit. However, H pylori infections mostly happen throughout childhood, so a vaccine ideally needs to protect for 10–15 years and more. If protection levels fall within a year—and possibly more in subsequent years—booster immunisations might be needed to maintain adequate protection levels, adding additional complexity to an already crowded childhood vaccination programme. Finally, a currently open question is whether the vaccine would work therapeutically. Although not essential, because infections begin early during childhood, any H pylori vaccine that also provides protection when delivered to infected people would be highly advantageous.
2
Despite these limitations and concerns, the proof of concept shown by Zeng and colleagues5 of vaccineinduced protection against H pylori infection is a major step towards a vaccine that protects against gastric cancer. This outcome will hopefully rekindle interest in this important topic, and encourage increased investment in progression of new projects through to advanced clinical trials. Philip Sutton Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia; and Centre for Animal Biotechnology, School of Veterinary and Agricultural Science, University of Melbourne, Parkville, VIC 3010, Australia [email protected] I have a patent relating to Helicobacter pylori vaccines issued, and a patent relating to H pylori vaccines pending. 1 2
3 4
5
6
7 8
9
Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001; 345: 784–89. Herrero R, Park JY, Forman D. The fight against gastric cancer—the IARC Working Group report. Best Pract Res Clin Gastroenterol 2014; 28: 1107–14. Sutton P, Chionh YT. Why can’t we make an effective vaccine against Helicobacter pylori? Expert Rev Vaccines 2013; 12: 433–41. Michetti P, Kreiss C, Kotloff KL, et al. Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori-infected adults. Gastroenterology 1999; 116: 804–12. Zeng M, Mao Z-H, Li J-X, et al. 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 2015; published online July 1. http://dx.doi.org/10.1016/S01406736(15)60310-5. Aebischer T, Bumann D, Epple HJ, et al. 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 2008; 57: 1065–72. Schwarz S, Morelli G, Kusecek B, et al. Horizontal versus familial transmission of Helicobacter pylori. PLoS Pathog 2008; 4: e1000180. Weyermann M, Rothenbacher D, Brenner H. Acquisition of Helicobacter pylori infection in early childhood: independent contributions of infected mothers, fathers, and siblings. Am J Gastroenterol 2009; 104: 182–89. Lewis DJ, Huo Z, Barnett S, et al. Transient facial nerve paralysis (Bell’s palsy) following intranasal delivery of a genetically detoxified mutant of Escherichia coli heat labile toxin. PLoS One 2009; 4: e6999.
www.thelancet.com Published online July 1, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60579-7
At last, vaccine-induced protection against Helicobacter pylori establishment of H pylori infection or eradicates at some time after colonisation is unknown); third, assess protection by measurement of subsequent acquisition of natural infection (rather than therapeutic vaccination or use of a challenge strain);4,6 fourth, use a fusion protein that might increase the efficiency of uptake and delivery of the vaccine antigen; and finally, vaccinate children. The age of the population in the present study is potentially important. H pylori transmission typically happens during childhood and new infections in adults are uncommon. The reason for this point is unknown, but might relate to a key transmission route to children from parents,7,8 or to physiological differences between children and adults that affect H pylori infectivity. Whatever the reason, a vaccine intended to prevent H pylori infection is perhaps more likely to reveal efficacy when tested in children, who are the main host initially colonised by these bacteria, than in adults. The most important achievement of Zeng and colleagues’ study5 might be to provide the first demonstration that vaccination can prevent H pylori infection in humans. However, whether an oral urease B subunit LTB vaccine will become a vaccine for widespread use against H pylori remains to be seen, in view of the challenges that still remain. First, vaccine recipients fasted for 2 h and were given a bicarbonate solution (presumably to buffer stomach acid and prevent vaccine degradation) before vaccination. Such an approach is unlikely to be feasible
www.thelancet.com Published online July 1, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60579-7
Published Online July 1, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)60579-7 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)60310-5
Science Photo Library
For a quarter of a century, countless attempts have been made to produce an effective vaccine against Helicobacter pylori, a major cause of peptic ulcer disease and gastric adenocarcinoma.1 An effective vaccine against H pylori is needed most for prevention of gastric adenocarcinoma, the third leading cause of cancer-related death worldwide.2 However, efforts to produce such a vaccine have so far failed, and H pylori vaccine research has slowed in the past few years. The main reason for this might have been disillusionment, arising from the inability to produce a vaccine that completely protects against the infection.3 Vaccine trials in mice have typically achieved only small reductions in the numbers of colonising H pylori. The story is similar in clinical trials, with only one showing potential efficacy, a small reduction in colonisation after therapeutic vaccination of infected volunteers.4 Hence, Ming Zeng and colleagues’ publication5 in The Lancet, of a randomised, double-blinded, placebo-controlled, phase 3 vaccine trial that shows a significant reduction in acquisition of natural H pylori infection, is a major advance. Zeng and colleagues orally vaccinated H pyloriuninfected children (aged 6–15 years) in China with three doses of a fusion protein composed of the B subunits of H pylori urease and heat-labile toxin (LTB) of Escherichia coli. After 1 year, 14 infections were recorded in 2199 children given the H pylori vaccine, compared with 50 infections in 2204 who received placebo, resulting in a vaccine efficacy of 71·8% (95% CI 48·2–85·6).5 Some study participants were followed up in a trial extension for an additional 2 years. Although H pylori acquisition continued to be lower in vaccinated than unvaccinated children, protection levels were less than in the first year (55% fewer new infections in vaccinated vs placebo), suggesting a possible waning of protection. That this urease B subunit-containing vaccine induced protection is intriguing, because previous vaccine trials, including some which contained H pylori urease (which includes the urease B subunit), were less successful.4,6 So what was different about this latest trial? Zeng and colleagues’ study5 is the first H pylori human vaccine trial to: first, reach phase 3 and thus immunise a large cohort; second, follow vaccine recipients over years, rather than months (whether vaccine-induced protection prevents
1
Comment
for a globally marketed vaccine, suggesting more formulation work and testing will be needed; the effects that modification of this protocol will have on vaccine efficacy also need to be established. Second, the use of LTB, which binds GM1 gangliosides, might raise regulatory eyebrows. When delivered nasally, the ganglioside-binding property of LTB can result in retrograde axonal transport, possibly to the facial nerve, such that even detoxified adjuvant is capable of causing Bell’s palsy.9 This very rare side-effect was responsible for withdrawal of an initially approved and released, nasally delivered influenza vaccine.9 Although oral delivery might help avoid such issues, these well documented side-effects are likely to attract scrutiny from regulatory authorities for any mucosal-delivered vaccine containing LTB. Third, there is an issue around the level of protection, which seems to wane after 1 year. In view of the high degree of morbidity and mortality associated with H pylori-associated gastric cancer, a vaccine that protects more than 70% of recipients from infection would be of enormous benefit. However, H pylori infections mostly happen throughout childhood, so a vaccine ideally needs to protect for 10–15 years and more. If protection levels fall within a year—and possibly more in subsequent years—booster immunisations might be needed to maintain adequate protection levels, adding additional complexity to an already crowded childhood vaccination programme. Finally, a currently open question is whether the vaccine would work therapeutically. Although not essential, because infections begin early during childhood, any H pylori vaccine that also provides protection when delivered to infected people would be highly advantageous.
2
Despite these limitations and concerns, the proof of concept shown by Zeng and colleagues5 of vaccineinduced protection against H pylori infection is a major step towards a vaccine that protects against gastric cancer. This outcome will hopefully rekindle interest in this important topic, and encourage increased investment in progression of new projects through to advanced clinical trials. Philip Sutton Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia; and Centre for Animal Biotechnology, School of Veterinary and Agricultural Science, University of Melbourne, Parkville, VIC 3010, Australia [email protected] I have a patent relating to Helicobacter pylori vaccines issued, and a patent relating to H pylori vaccines pending. 1 2
3 4
5
6
7 8
9
Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001; 345: 784–89. Herrero R, Park JY, Forman D. The fight against gastric cancer—the IARC Working Group report. Best Pract Res Clin Gastroenterol 2014; 28: 1107–14. Sutton P, Chionh YT. Why can’t we make an effective vaccine against Helicobacter pylori? Expert Rev Vaccines 2013; 12: 433–41. Michetti P, Kreiss C, Kotloff KL, et al. Oral immunization with urease and Escherichia coli heat-labile enterotoxin is safe and immunogenic in Helicobacter pylori-infected adults. Gastroenterology 1999; 116: 804–12. Zeng M, Mao Z-H, Li J-X, et al. 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 2015; published online July 1. http://dx.doi.org/10.1016/S01406736(15)60310-5. Aebischer T, Bumann D, Epple HJ, et al. 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 2008; 57: 1065–72. Schwarz S, Morelli G, Kusecek B, et al. Horizontal versus familial transmission of Helicobacter pylori. PLoS Pathog 2008; 4: e1000180. Weyermann M, Rothenbacher D, Brenner H. Acquisition of Helicobacter pylori infection in early childhood: independent contributions of infected mothers, fathers, and siblings. Am J Gastroenterol 2009; 104: 182–89. Lewis DJ, Huo Z, Barnett S, et al. Transient facial nerve paralysis (Bell’s palsy) following intranasal delivery of a genetically detoxified mutant of Escherichia coli heat labile toxin. PLoS One 2009; 4: e6999.
www.thelancet.com Published online July 1, 2015 http://dx.doi.org/10.1016/S0140-6736(15)60579-7
