Brickley, Elizabeth B

Wright, Peter F

LSHTM Research Online

Brickley, EB; Wright, PF (2017) Maximising the impact of inactivatedpolio vaccines. The Lancet infectious diseases, 17 (7). pp. 680-681.ISSN 1473-3099 DOI: https://doi.org/10.1016/S1473-3099(17)30236-0Downloaded from: http://researchonline.lshtm.ac.uk/4645643/DOI: 10.1016/S1473-3099(17)30236-0Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: http://creativecommons.org/licenses/by-nc-nd/2.5/Comment680 www.thelancet.com/infection   Vol 17   July 20171 Vickers RJ, Tillotson GS, Nathan R, et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis 2017; published online April 28. http://dx.doi.org/10.1016/S1473-3099(17)30235-9.2 Dingle KE, Didelot X, Quan TP, et al. Effects of control interventions on Clostridium difficile infection in England: an observational study. Lancet Infect Dis 2017; 17: 411–21.3 Mitchell BG, Gardner A. Mortality and Clostridium difficile: a review. Antimicrob Resis Infect Control 2012; 1: 20.4 Van Kleef E, Green N, Goldenberg SD, et al. Excess length of stay and mortality due to Clostridium difficile infection: a multi-state modelling approach. J Hosp Infect 2014; 88: 213–17.5 Hensgens MP, Goorhuis A, Dekkers OM, Kuijper EJ. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother 2012; 67: 742–48.6 Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review. J Antimicrob Chemother 2003; 51: 1339–50.7 Abou Chakra CN, Pepin J, Sirard S, Valiquette L. Risk factors for recurrence, complications and mortality in Clostridium difficile infection: a systematic review. PLoS One 2014; 9: e98400.8 Kelly, CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect 2012; 18: 21–27.9 Barkin JA, Sussman DA, Fifadara N, Barkin JS. Clostridium difficile infection and patient-specific antimicrobial resistance testing reveals a high metronidazole resistance rate. Dig Dis Sci 2017; 62: 1035–42.10 Stevens WV, Nelson RE, Schwab-Daughterty EM, et al. Comparative effectiveness of vancomycin and metronidazole for the prevention of recurrence and death in patients with Clostridium difficile infection. JAMA Intern Med 2017; 177: 546–53.11 Goldenberg SD, Brown S, Edwards L, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations. Eur J Clin Microbiol Infect Dis 2016; 35: 251–59.12 Shah DN, Aitken SL, Barragan LF, et al. Economic burden of primary compared with recurrent Clostridium difficile infection in hospitalized patients: a prospective cohort study. J Hosp Infect 2016; 93: 286–89.Maximising the impact of inactivated polio vaccinesWith the globally coordinated switch from the trivalent oral polio vaccine (OPV) to the bivalent OPV in April, 2016, the international public health community entered a new chapter in the endgame of polio. Although OPV has served as the cornerstone of polio eradication efforts over the past 30 years, trivalent inactivated polio vaccine (IPV) has re-ascended to prominence in the past year, now acting as the sole source of protective immunity against type 2 poliovirus in routine immunisation programmes. Despite its immense public health value, the global supply of IPV is failing to meet demand. The October, 2016, meeting of the Strategic Advisory Group of Experts on Immunization cautioned that, “the IPV supply situation is further deteriorating; 50 countries are experiencing delays in supply or stock-outs, a situation which is likely to persist until 2018”.1Given the existing resource constraints, pragmatic solutions are urgently needed to maximise the impact of IPVs during the transitional and post-OPV immunisation era. In The Lancet Infectious Diseases, Birgit Thierry-Carstensen and colleagues2 report one such novel strategy in the form of reduced-dose IPVs administered intramuscularly with an aluminium hydroxide (Al) adjuvant. The three IPV-Al candidates were formulated at one-third, one-fifth, and one-tenth the concentration of standard IPV and administered to healthy children living in the Dominican Republic at 6, 10, and 14 weeks of age. The results of the well conducted phase 2 trial indicate that the antigen-sparing IPV-Als were able to achieve substantial (ie, ≥75%) seroconversion against the three serotypes of polio after only two vaccine doses. Promisingly, after three doses, all three formulations of IPV-Als achieved more than 94% seroconversion to poliovirus types 1, 2, and 3, and the seroresponses were non-inferior to those of the standard IPV, which was administered unadjuvanted, but at up to ten-fold higher concentrations.Enhancing the immunogenicity of IPVs is an important achievement in view of the ongoing shortfalls in IPV production by global pharmaceutical firms. Moving forward, an antigen-sparing IPV with adjuvant would be a welcome addition to the expanding portfolio of alternative IPV approaches under development, which also includes fractional (ie, reduced-volume) intradermal IPVs3,4 and enhanced potency high dose IPVs5 that might limit the number of serial doses required to uniformly induce immunity. Overall, dose-sparing IPV strategies have the potential to reduce costs of immunisation activities,6 facilitate the protection of individuals during outbreaks by enabling both prompt responses and high levels of coverage,7 and stretch dwindling vaccine supplies. However, selecting and then operationally optimising an IPV strategy for a specific context will be challenged by a number of logistical barriers (eg, scalability and costs of vaccine production and storage, availability of trained vaccinators, procurement of immunisation devices) and immunological considerations (eg, scheduling to mitigate interference by maternal antibodies, inducing seroprotection of an appropriate magnitude and duration).8Garo/Phanie/Science Photo LibraryPublished Online April 25, 2017 http://dx.doi.org/10.1016/ S1473-3099(17)30236-0See Article page 745Commentwww.thelancet.com/infection   Vol 17   July 2017 681In preparing the global public health system to withstand shortages in IPV supply moving forward, it is also important to give due consideration to a limitation of all IPVs—namely, that inactivated vaccines appear to have a limited capacity to induce intestinal immunity against polio. There is no question that serum antibodies produced in response to IPVs are able to successfully protect vaccinees against paralytic polio by inhibiting viraemia and entry into the CNS. Perhaps less appreciated is that with polio—and probably many other pathogens replicating at mucosal surfaces—a vaccine’s ability to induce mucosal immunity is tightly linked to the vaccine’s capacity to block viral shedding and, thereby, potential onward transmission. Mounting evidence from OPV challenge trials5,9,10 indicates that, when delivered in a primary vaccine series, IPV seems to have only limited effects on the duration and degree of viral shedding. By contrast, the intestinal immunity induced by live, oral vaccines is close to achieving the ideal of sterilising immunity.10–12 Ultimately, blocking transmission (eg, via integrated OPV-IPV intestinal immune-boosting strategies13,14 and the development of the more highly attenuated and genetically stable novel OPVs) and thus reducing IPV demand for outbreak control is also a paramount consideration for capitalising on the utility of IPVs under the reality of existing supply limitations.Eradication of polio is tantalisingly close. In the final steps toward eradication and for the post-eradication era, there is a need for as many arrows in the quiver as possible, and it would be valuable to add aluminium hydroxide-enhanced IPV to that arsenal.Elizabeth B Brickley, *Peter F WrightDepartment of Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA (EBB); and Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA (PFW) Peter.F.Wright@hitchcock.orgWe declare no competing interests.© The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.1 WHO. Weekly epidemiological record, 2 December 2016. Geneva: World Health Organization, 2016: 561–84.2 Rivera L, Pedersen RS, Peña L, et al. Immunogenicity and safety of three aluminium hydroxide adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) compared with standard IPV in young infants in the Dominican Republic: a phase 2, non-inferiority, observer-blinded, randomised, and controlled dose investigation trial. Lancet Infect Dis 2017; published online April 25. http://dx.doi.org/10.1016/S1473-3099(17)30177-9.3 Resik S, Tejeda A, Lago PM, et al. Randomized controlled clinical trial of fractional doses of inactivated poliovirus vaccine administered intradermally by needle-free device in Cuba. J Infect Dis 2010; 201: 1344–52.4 Mohammed AJ, AlAwaidy S, Bawikar S, et al. Fractional doses of inactivated poliovirus vaccine in Oman. N Engl J Med 2010; 362: 2351–59.5 Saez-Llorens X, Clemens R, Leroux-Roels G, et al. Immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine in infants: a comparative, observer-blind, randomised, controlled trial. Lancet Infect Dis 2016; 16: 321–30.6 Hickling J, Jones R, Nundi N. Improving the affordability of inactivated poliovirus vaccines (IPV) for use in low- and middle-income countries: an economic analysis of strategies to reduce the cost of routine IPV immunization. Seattle, WA: Program for Appropriate Technology in Health (PATH), 2010.7 Bahl S, Verma H, Bhatnagar P, et al. Fractional-dose inactivated poliovirus vaccine immunization campaign—Telangana State, India, June 2016. MMWR Morb Mortal Wkly Rep 2016; 65: 859–63.8 Estivariz CF, Pallansch MA, Anand A, et al. Poliovirus vaccination options for achieving eradication and securing the endgame. Curr Opin Virol 2013; 3: 309–15.9 O’Ryan M, Bandyopadhyay AS, Villena R, et al. Inactivated poliovirus vaccine given alone or in a sequential schedule with bivalent oral poliovirus vaccine in Chilean infants: a randomised, controlled, open-label, phase 4, non-inferiority study. Lancet Infect Dis 2015; 15: 1273–82.10 Hird TR, Grassly NC. Systematic review of mucosal immunity induced by oral and inactivated poliovirus vaccines against virus shedding following oral poliovirus challenge. PLoS Pathog 2012; 8: e1002599.11 Asturias EJ, Bandyopadhyay AS, Self S, et al. Humoral and intestinal immunity induced by new schedules of bivalent oral poliovirus vaccine and one or two doses of inactivated poliovirus vaccine in Latin American infants: an open-label randomised controlled trial. Lancet 2016; 388: 158–69.12 Wright PF, Connor RI, Wieland-Alter WF, et al. Vaccine-induced mucosal immunity to poliovirus: analysis of cohorts from an open-label, randomised controlled trial in Latin American infants. Lancet Infect Dis 2016; 16: 1377–84.13 John J, Giri S, Karthikeyan AS, et al. Effect of a single inactivated poliovirus vaccine dose on intestinal immunity against poliovirus in children previously given oral vaccine: an open-label, randomised controlled trial. Lancet 2014; 384: 1505–12.14 Jafari H, Deshpande JM, Sutter RW, et al. Polio eradication. Efficacy of inactivated poliovirus vaccine in India. Science 2014; 345: 922–25.Should we continue to monitor 4CMenB coverage with MATS?A long research process has led to development of a multicomponent vaccine indicated for prevention of invasive meningococcal disease associated with sero-group B Neisseria meningitidis (4CMenB; Bexsero, GlaxoSmithKline Vaccines, Siena, Italy).1 The vaccine was licensed despite no clinical trial data for efficacy because of the very low prevalence of the disease. Similar to conjugate vaccines against other serogroups, the licensure process was based on data obtained through correlates of protection.2 For polysaccharide conjugate Published Online March 30, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30174-3See Articles page 754

Maximising the impact of inactivated polio vaccines.

Elizabeth B Brickley

Peter F Wright

Crossref

The Lancet Infectious Diseases