The safety and immunogenicity of two novel live attenuated monovalent (serotype 2) oral poliovirus vaccines in healthy adults: a double-blind, single-centre phase 1 study

Abstract

Background: Use of oral live-attenuated polio vaccines (OPV), and injected inactivated polio vaccines (IPV) has almost achieved global eradication of wild polio viruses. To address the goals of achieving and maintaining global eradication and minimising the risk of outbreaks of vaccine-derived polioviruses, we tested novel monovalent oral type-2 poliovirus (OPV2) vaccine candidates that are genetically more stable than existing OPVs, with a lower risk of reversion to neurovirulence. Our study represents the first in-human testing of these two novel OPV2 candidates. We aimed to evaluate the safety and immunogenicity of these vaccines, the presence and extent of faecal shedding, and the neurovirulence of shed virus.

Methods: In this double-blind, single-centre phase 1 trial, we isolated participants in a purpose-built containment facility at the University of Antwerp Hospital (Antwerp, Belgium), to minimise the risk of environmental release of the novel OPV2 candidates. Participants, who were recruited by local advertising, were adults (aged 18-50 years) in good health who had previously been vaccinated with IPV, and who would not have any contact with immunosuppressed or unvaccinated people for the duration of faecal shedding at the end of the study. The first participant randomly chose an envelope containing the name of a vaccine candidate, and this determined their allocation; the next 14 participants to be enrolled in the study were sequentially allocated to this group and received the same vaccine. The subsequent 15 participants enrolled after this group were allocated to receive the other vaccine. Participants and the study staff were masked to vaccine groups until the end of the study period. Participants each received a single dose of one vaccine candidate (candidate 1, S2/cre5/S15domV/rec1/hifi3; or candidate 2, S2/S15domV/CpG40), and they were monitored for adverse events, immune responses, and faecal shedding of the vaccine virus for 28 days. Shed virus isolates were tested for the genetic stability of attenuation. The primary outcomes were the incidence and type of serious and severe adverse events, the proportion of participants showing viral shedding in their stools, the time to cessation of viral shedding, the cell culture infective dose of shed virus in virus-positive stools, and a combined index of the prevalence, duration, and quantity of viral shedding in all participants. This study is registered with EudraCT, number 2017-000908-21 and ClinicalTrials.gov, number NCT03430349.

Findings: Between May 22 and Aug 22, 2017, 48 volunteers were screened, of whom 15 (31%) volunteers were excluded for reasons relating to the inclusion or exclusion criteria, three (6%) volunteers were not treated because of restrictions to the number of participants in each group, and 30 (63%) volunteers were sequentially allocated to groups (15 participants per group). Both novel OPV2 candidates were immunogenic and increased the median blood titre of serum neutralising antibodies; all participants were seroprotected after vaccination. Both candidates had acceptable tolerability, and no serious adverse events occurred during the study. However, severe events were reported in six (40%) participants receiving candidate 1 (eight events) and nine (60%) participants receiving candidate 2 (12 events); most of these events were increased blood creatinine phosphokinase but were not accompanied by clinical signs or symptoms. Vaccine virus was detected in the stools of 15 (100%) participants receiving vaccine candidate 1 and 13 (87%) participants receiving vaccine candidate 2. Vaccine poliovirus shedding stopped at a median of 23 days (IQR 15-36) after candidate 1 administration and 12 days (1-23) after candidate 2 administration. Total shedding, described by the estimated median shedding index (50% cell culture infective dose/g), was observed to be greater with candidate 1 than candidate 2 across all participants (2·8 [95% CI 1·8-3·5] vs 1·0 [0·7-1·6]). Reversion to neurovirulence, assessed as paralysis of transgenic mice, was low in isolates from those vaccinated with both candidates, and sequencing of shed virus indicated that there was no loss of attenuation in domain V of the 5'-untranslated region, the primary site of reversion in Sabin OPV.

Interpretation: We found that the novel OPV2 candidates were safe and immunogenic in IPV-immunised adults, and our data support the further development of these vaccines to potentially be used for maintaining global eradication of neurovirulent type-2 polioviruses.

Funding: Bill & Melinda Gates Foundation.

Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

Trial profile

Figure 2

Viral shedding of the two novel oral type-2 poliovirus vaccine candidates Data are the number of PCR-positive stool samples and the log10(CCID50/g) after administration on day 0. Participants who had ceased shedding were included, at a value of 0, in the computation of the mean log10(CCID50/g). CCID50=50% cell culture infectious dose.

References

1. 1. WHO Global Polio Eradication Initiative Global eradication of wild poliovirus type 2 declared. Sept 20, 2015.
   2. WHO Global Polio Eradication Initiative. Global eradication of wild poliovirus type 2 declared. Sept 20, 2015. (accessed Nov 29, 2018).
2. 1. Strategic Advisory Group of Experts Summary of the April 2017 meeting of the Strategic Advisory Group of Experts on Immunization.
   2. Strategic Advisory Group of Experts. Summary of the April 2017 meeting of the Strategic Advisory Group of Experts on Immunization. (accessed Nov 29, 2018).
3. 1. Previsani N, Singh H, St Pierre J. Progress toward containment of poliovirus type 2—worldwide, 2017. MMWR Morb Mortal Wkly Rep. 2017;66:649–652.
   2. Previsani N, Singh H, St Pierre J, et al. Progress toward containment of poliovirus type 2—worldwide, 2017. MMWR Morb Mortal Wkly Rep 2017; 66: 649–52.
4. 1. Sutter RW, Kew OM, Cochi SL, Aylward RB. Poliovirus vaccine-live. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. Elsevier Saunders; Philadelphia: 2012. pp. 598–645.
   2. Sutter RW, Kew OM, Cochi SL, Aylward RB. Poliovirus vaccine-live. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. Philadelphia: Elsevier Saunders, 2012: 598–645.
5. 1. WHO Global Polio Eradication Initiative Fact sheet—February 2015: vaccine-associated paralytic polio (VAPP) and vaccine-derived poliovirus (VDPV)
   2. WHO Global Polio Eradication Initiative. Fact sheet—February 2015: vaccine-associated paralytic polio (VAPP) and vaccine-derived poliovirus (VDPV). (accessed Nov 29, 2018).
6. 1. Chandler J. Fighting a polio outbreak in Papua New Guinea. Lancet. 2018;392:2155–2156.
   2. Chandler J. Fighting a polio outbreak in Papua New Guinea. Lancet 2018; 392: 2155–56.
7. 1. Jorba J, Diop OM, Iber J. Update on vaccine-derived polioviruses—worldwide, January 2017–June 2018. MMWR Morb Mortal Wkly Rep. 2018;67:1189–1194.
   2. Jorba J, Diop OM, Iber J, et al. Update on vaccine-derived polioviruses—worldwide, January 2017–June 2018. MMWR Morb Mortal Wkly Rep 2018; 67: 1189–94.
8. 1. Duintjer Tebbens RJ, Thompson KM. Polio endgame risks and the possibility of restarting the use of oral poliovirus vaccine. Expert Rev Vaccines. 2018;17:739–751.
   2. Duintjer Tebbens RJ, Thompson KM. Polio endgame risks and the possibility of restarting the use of oral poliovirus vaccine. Expert Rev Vaccines 2018; 17: 739–51.
9. 1. Fu R, Altamirano J, Sarnquist CC, Maldonado YA, Andrews JR. Assessing the risk of vaccine-derived outbreaks after reintroduction of oral poliovirus vaccine in postcessation settings. Clin Infect Dis. 2018;67(suppl 1):S26–S34.
   2. Fu R, Altamirano J, Sarnquist CC, Maldonado YA, Andrews JR. Assessing the risk of vaccine-derived outbreaks after reintroduction of oral poliovirus vaccine in postcessation settings. Clin Infect Dis 2018; 67 (suppl 1): S26–34.
10. 1. 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
    2. 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. 1. Bandyopadhyay AS, Modlin JF, Wenger J, Gast C. Immunogenicity of new primary immunization schedules with inactivated poliovirus vaccine and bivalent oral polio vaccine for the polio endgame: a review. Clin Infect Dis. 2018;67(suppl 1):S35–S41.
    2. Bandyopadhyay AS, Modlin JF, Wenger J, Gast C. Immunogenicity of new primary immunization schedules with inactivated poliovirus vaccine and bivalent oral polio vaccine for the polio endgame: a review. Clin Infect Dis 2018; 67 (suppl 1): S35–41.
12. 1. WHO WHO Global Action Plan to minimize poliovirus facility-associated risk after type-specific eradication of wild polioviruses and sequential cessation of oral polio vaccine use: GAPIII. 2015.
    2. WHO. WHO Global Action Plan to minimize poliovirus facility-associated risk after type-specific eradication of wild polioviruses and sequential cessation of oral polio vaccine use: GAPIII. 2015. (accessed Nov 29, 2018).
13. 1. WHO Standard operating procedure: neurovirulence test of types 1, 2 or 3 live attenuated poliomyelitis vaccines (oral) in monkeys. 2012.
    2. WHO. Standard operating procedure: neurovirulence test of types 1, 2 or 3 live attenuated poliomyelitis vaccines (oral) in monkeys. 2012. (accessed Nov 29, 2018).
14. 1. Kilpatrick DR, Yang CF, Ching K. Rapid group-, serotype-, and vaccine strain-specific identification of poliovirus isolates by real-time reverse transcription-PCR using degenerate primers and probes containing deoxyinosine residues. J Clin Microbiol. 2009;47:1939–1941.
    2. Kilpatrick DR, Yang CF, Ching K, et al. Rapid group-, serotype-, and vaccine strain-specific identification of poliovirus isolates by real-time reverse transcription-PCR using degenerate primers and probes containing deoxyinosine residues. J Clin Microbiol 2009; 47: 1939–41.
15. 1. Esona MD, McDonald S, Kamili S, Kerin T, Gautam R, Bowen MD. Comparative evaluation of commercially available manual and automated nucleic acid extraction methods for rotavirus RNA detection in stools. J Virol Methods. 2013;194:242–249.
    2. Esona MD, McDonald S, Kamili S, Kerin T, Gautam R, Bowen MD. Comparative evaluation of commercially available manual and automated nucleic acid extraction methods for rotavirus RNA detection in stools. J Virol Methods 2013; 194: 242–49.
16. 1. Weldon WC, Oberste MS, Pallansch MA. Standardized methods for detection of poliovirus antibodies. In: Martín J, editor. Poliovirus: Methods in Molecular Biology. Humana Press; New York: 2016. pp. 145–176.
    2. Weldon WC, Oberste MS, Pallansch MA. Standardized methods for detection of poliovirus antibodies. In: Poliovirus: Methods in Molecular Biology. Martín J, ed. New York: Humana Press, 2016; 145–76.
17. 1. WHO Standard operating procedure: neurovirulence test of types 1, 2 or 3 live attenuated poliomyelitis vaccines (oral) in transgenic mice susceptible to poliovirus. 2017.
    2. WHO. Standard operating procedure: neurovirulence test of types 1, 2 or 3 live attenuated poliomyelitis vaccines (oral) in transgenic mice susceptible to poliovirus. 2017. (accessed Nov 29, 2018).
18. 1. Asturias EJ, Bandyopadhyay AS, Self S. 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;388:158–169.
    2. 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.
19. 1. Sarcey E, Serres A, Tindy F. Quantifying low-frequency revertants in oral poliovirus vaccine using next generation sequencing. J Virol Methods. 2017;246:75–80.
    2. Sarcey E, Serres A, Tindy F, et al. Quantifying low-frequency revertants in oral poliovirus vaccine using next generation sequencing. J Virol Methods 2017; 246: 75–80.
20. 1. O'Ryan M, Bandyopadhyay AS, Villena R. 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;15:1273–1282.
    2. 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.
21. 1. Lilleng H, Abeler K, Johnsen SH. Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study. Neuromuscul Disord. 2011;21:494–500.
    2. Lilleng H, Abeler K, Johnsen SH, et al. Variation of serum creatine kinase (CK) levels and prevalence of persistent hyperCKemia in a Norwegian normal population. The Tromsø Study. Neuromuscul Disord 2011; 21: 494–500.
22. 1. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ. 2005;172:367–379.
    2. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005; 172: 367–79.
23. 1. Moghadam-Kia S, Oddis CV, Aggarwal R. Approach to asymptomatic creatine kinase elevation. Cleve Clin J Med. 2016;83:37–42.
    2. Moghadam-Kia S, Oddis CV, Aggarwal R. Approach to asymptomatic creatine kinase elevation. Cleve Clin J Med 2016; 83: 37–42.
24. 1. 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
    2. 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.
25. 1. Ren RB, Moss EG, Racaniello VR. Identification of two determinants that attenuate vaccine-related type 2 poliovirus. J Virol. 1991;65:1377–1382.
    2. Ren RB, Moss EG, Racaniello VR. Identification of two determinants that attenuate vaccine-related type 2 poliovirus. J Virol 1991; 65: 1377–82.
26. 1. Macadam AJ, Pollard SR, Ferguson G. Genetic basis of attenuation of the Sabin type 2 vaccine strain of poliovirus in primates. Virology. 1993;192:18–26.
    2. Macadam AJ, Pollard SR, Ferguson G, et al. Genetic basis of attenuation of the Sabin type 2 vaccine strain of poliovirus in primates. Virology 1993; 192: 18–26.
27. 1. Laassri M, Dragunsky E, Enterline J. Genetic analysis of vaccine-derived poliovirus strains in stool specimens by combination of full-length PCR and oligonucleotide microarray hybridization. J Clin Microbiol. 2005;43:2886–2894.
    2. Laassri M, Dragunsky E, Enterline J, et al. Genetic analysis of vaccine-derived poliovirus strains in stool specimens by combination of full-length PCR and oligonucleotide microarray hybridization. J Clin Microbiol 2005; 43: 2886–94.
28. 1. Stern A, Yeh MT, Zinger T. The evolutionary pathway to virulence of an RNA virus. Cell. 2017;169:35–46.
    2. Stern A, Yeh MT, Zinger T, et al. The evolutionary pathway to virulence of an RNA virus. Cell 2017; 169: 35–46.
29. 1. Brickley EB, Strauch CB, Wieland-Alter WF. Intestinal immune responses to type 2 oral polio vaccine (OPV) challenge in infants previously immunized with bivalent OPV and either high-dose or standard inactivated polio vaccine. J Infect Dis. 2018;217:371–380.
    2. Brickley EB, Strauch CB, Wieland-Alter WF, et al. Intestinal immune responses to type 2 oral polio vaccine (OPV) challenge in infants previously immunized with bivalent OPV and either high-dose or standard inactivated polio vaccine. J Infect Dis 2018; 217: 371–80.