Inactivated poliovirus type 2 vaccine delivered to rat skin via high density microprojection array elicits potent neutralising antibody responses.
ABSTRACT: Polio eradication is progressing rapidly, and the live attenuated Sabin strains in the oral poliovirus vaccine (OPV) are being removed sequentially, starting with type 2 in April 2016. For risk mitigation, countries are introducing inactivated poliovirus vaccine (IPV) into routine vaccination programs. After April 2016, monovalent type 2 OPV will be available for type 2 outbreak control. Because the current IPV is not suitable for house-to-house vaccination campaigns (the intramuscular injections require health professionals), we developed a high-density microprojection array, the Nanopatch, delivered monovalent type 2 IPV (IPV2) vaccine to the skin. To assess the immunogenicity of the Nanopatch, we performed a dose-matched study in rats, comparing the immunogenicity of IPV2 delivered by intramuscular injection or Nanopatch immunisation. A single dose of 0.2 D-antigen units of IPV2 elicited protective levels of poliovirus antibodies in 100% of animals. However, animals receiving IPV2 by IM required at least 3 immunisations to reach the same neutralising antibody titres. This level of dose reduction (1/40th of a full dose) is unprecedented for poliovirus vaccine delivery. The ease of administration coupled with the dose reduction observed in this study points to the Nanopatch as a potential tool for facilitating inexpensive IPV for mass vaccination campaigns.
Project description:To secure a polio-free world, the live attenuated oral poliovirus vaccine (OPV) will eventually need to be replaced with inactivated poliovirus vaccines (IPV). However, current IPV delivery is less suitable for campaign use than OPV, and more expensive. We are progressing a microarray patch delivery platform, the Nanopatch, as an easy-to-use device to administer vaccines, including IPV. The Nanopatch contains an ultra-high density array (10,000/cm2) of short (~230 ?m) microprojections that delivers dry coated vaccine into the skin. Here, we compare the relative immunogenicity of Nanopatch immunisation versus intramuscular injection in rats, using monovalent and trivalent formulations of IPV. Nanopatch delivery elicits faster antibody response kinetics, with high titres of neutralising antibody after just one (IPV2) or two (IPV1 and IPV3) immunisations, while IM injection requires two (IPV2) or three (IPV1 and IPV3) immunisations to induce similar responses. Seroconversion to each poliovirus type was seen in 100% of rats that received ~1/40th of a human dose of IPV delivered by Nanopatch, but not in rats given ~1/8th or ~1/40th dose by IM injection. Ease of administration coupled with dose reduction observed in this study suggests the Nanopatch could facilitate inexpensive IPV vaccination in campaign settings.
Project description:Background:In Pakistan and other countries using oral polio vaccine (OPV), immunity to type 2 poliovirus is now maintained by a single dose of inactivated polio vaccine (IPV) in routine immunization, supplemented in outbreak settings by monovalent OPV type 2 (mOPV2) and IPV. While well-studied in clinical trials, population protection against poliovirus type 2 achieved in routine and outbreak settings is generally unknown. Methods:We conducted two phases of a population-based serological survey of 7940 children aged 6-11 months old, between November 2016 and October 2017 from 13 polio high-risk locations in Pakistan. Results:Type 2 seroprevalence was 50% among children born after trivalent OPV (tOPV) withdrawal (April 2016), with heterogeneity across survey areas. Supplementary immunization activities (SIAs) with mOPV2 followed by IPV improved population immunity, varying from 89% in Pishin to 64% in Killa Abdullah, with little observed marginal benefit of subsequent campaigns. In the other high-risk districts surveyed, a single SIA with IPV was conducted and appeared to improve immunity to 57% in Karachi to 84% in Khyber. Conclusions:Our study documents declining population immunity following trivalent OPV withdrawal in Pakistan, and wide heterogeneity in the population impact of supplementary immunization campaigns. Differences between areas, attributable to vaccination campaign coverage, were far more important for type 2 humoral immunity than the number of vaccination campaigns or vaccines used. This emphasizes the importance of immunization campaign coverage for type 2 outbreak response in the final stages of polio eradication. Given the declining type 2 immunity in new birth cohorts it is also recommended that 2 or more doses of IPV should be introduced in the routine immunization program of Pakistan.
Project description:Inactivated poliovirus vaccine (IPV) may be used in mass vaccination campaigns during the final stages of polio eradication. It is also likely to be adopted by many countries following the coordinated global cessation of vaccination with oral poliovirus vaccine (OPV) after eradication. The success of IPV in the control of poliomyelitis outbreaks will depend on the degree of nasopharyngeal and intestinal mucosal immunity induced against poliovirus infection. We performed a systematic review of studies published through May 2011 that recorded the prevalence of poliovirus shedding in stool samples or nasopharyngeal secretions collected 5-30 days after a "challenge" dose of OPV. Studies were combined in a meta-analysis of the odds of shedding among children vaccinated according to IPV, OPV, and combination schedules. We identified 31 studies of shedding in stool and four in nasopharyngeal samples that met the inclusion criteria. Individuals vaccinated with OPV were protected against infection and shedding of poliovirus in stool samples collected after challenge compared with unvaccinated individuals (summary odds ratio [OR] for shedding 0.13 (95% confidence interval [CI] 0.08-0.24)). In contrast, IPV provided no protection against shedding compared with unvaccinated individuals (summary OR 0.81 [95% CI 0.59-1.11]) or when given in addition to OPV, compared with individuals given OPV alone (summary OR 1.14 [95% CI 0.82-1.58]). There were insufficient studies of nasopharyngeal shedding to draw a conclusion. IPV does not induce sufficient intestinal mucosal immunity to reduce the prevalence of fecal poliovirus shedding after challenge, although there was some evidence that it can reduce the quantity of virus shed. The impact of IPV on poliovirus transmission in countries where fecal-oral spread is common is unknown but is likely to be limited compared with OPV.
Project description:In 2014, inactivated poliovirus vaccine (IPV) campaigns were implemented in Nigeria and Pakistan after clinical trials showed that IPV boosts intestinal immunity in children previously given oral poliovirus vaccine (OPV). We estimated the effect of these campaigns by using surveillance data collected during January 2014-April 2016. In Nigeria, campaigns with IPV and trivalent OPV (tOPV) substantially reduced the incidence of poliomyelitis caused by circulating serotype-2 vaccine-derived poliovirus (incidence rate ratio [IRR] 0.17 for 90 days after vs. 90 days before campaigns, 95% CI 0.04-0.78) and the prevalence of virus in environmental samples (prevalence ratio [PR] 0.16, 95% CI 0.02-1.33). Campaigns with tOPV alone resulted in similar reductions (IRR 0.59, 95% CI 0.18-1.97; PR 0.45, 95% CI 0.21-0.95). In Pakistan, the effect of IPV+tOPV campaigns on wild-type poliovirus was not significant. Results suggest that administration of IPV alongside OPV can decrease poliovirus transmission if high vaccine coverage is achieved.
Project description:BACKGROUND:Outbreaks of circulating vaccine derived polioviruses type 2 (cVDPV2) remain a risk to poliovirus eradication in an era without live poliovirus vaccine containing type 2 in routine immunization. We evaluated existing outbreak response strategies recommended by the World Health Organization (WHO) for control of cVDPV2 outbreaks. METHODS:Seronegative children for poliovirus type 2 (PV2) at 22?weeks of life were assigned to one of four study groups and received respectively (1) one dose of trivalent oral poliovirus vaccine (tOPV); (2) monovalent OPV 2 (mOPV2); (3) tOPV together with a dose of inactivated poliovirus vaccine (IPV); or (4) mOPV2 with monovalent high-potency IPV type 2. Stool and blood samples were collected and assessed for presence of PV2 (stool) and anti-polio antibodies (sera). RESULTS:We analyzed data from 265 children seronegative for PV2. Seroconversion to PV2 was achieved in 48, 76, 98 and 100% in Groups 1-4 respectively. mOPV2 was more immunogenic than tOPV alone (p?<?0.001); and OPV in combination with IPV was more immunogenic than OPV alone (p?<?0.001). There were 33%, 67%, 20% and 43% PV2 excretors in Groups 1-4 respectively. mOPV2 resulted in more prevalent shedding of PV2 than when tOPV was used (p?<?0.001); and tOPV together with IPV resulted in lower excretion of PV2 than tOPV alone (p?=?0.046). CONCLUSION:mOPV2 was a more potent vaccine than tOPV. Adding IPV to OPV improved immunological response; adding IPV also seemed to have shortened the duration of PV2 shedding. mIPV2 did not provide measurable improvement of immune response when compared to conventional IPV. WHO recommendation to use mOPV2 as a vaccine of first choice in cVDPV2 outbreak response was supported by our findings. Clinical Trial registry number: NCT02189811.
Project description:As progress toward global poliovirus eradication continues, more and more countries are moving away from use of oral poliovirus vaccines (OPV) to inactivated poliovirus vaccines (IPV) in national vaccination schedules. Reduction of antigen dose in IPV could increase manufacturing capacity and facilitate the change from OPV to IPV. Combination vaccines reduce the number of injections required to complete vaccination, thus playing an important role in maintaining high vaccine coverage with good public acceptability. Three formulations of a combined, candidate hexavalent diphtheria-tetanus-whole cell pertussis-hepatitis B-inactivated poliovirus-Hemophilus influenzae type b conjugate vaccine (DTPw-HBV-IPV/Hib, GlaxoSmithKline Biologicals) differing only in IPV antigen content (full-dose, half-dose and one-third dose as compared with available stand-alone IPV vaccines), were evaluated when administered to healthy toddlers. Controls received separately administered licensed DTPw-HBV/Hib and IPV vaccines. Immunogenicity was assessed before and one month after vaccination. Safety and reactogenicity data were assessed for 30 d after vaccination. A total of 312 Filipino children were vaccinated in their second year of life. Each DTPw-HBV-IPV/Hib formulation was non-inferior to control in terms of pre-defined criteria for IPV immunogenicity. Post-vaccination GMTs against each poliovirus type were increased between 4.2- and 37.9-fold over pre-vaccination titers. Non-inferiority to other vaccine antigens was also demonstrated. The safety profile of the 3 DTPw-HBV-IPV/Hib formulations resembled licensed DTPw-HBV/Hib Kft and IPV in terms of the frequency and intensity of adverse reactions after vaccination. Further investigation of DTPw-HBV-IPV/Hib containing reduced quantity of IPV antigen for primary vaccination in infants is warranted. This study is registered at www.clinicaltrials.gov NCT number: NCT01106092.
Project description:The World Health Organization has recommended that all 124 countries currently using only oral poliovirus vaccine (OPV) introduce at least 1 dose of inactivated poliovirus vaccine (IPV) before the global withdrawal of serotype 2 OPV in 2016. A 1- or 2-dose schedule, potentially administered intradermally with reduced antigen content, may make this affordable.A systematic review and meta-analysis of studies documenting seroconversion after 1 or 2, full or fractional (1/5) doses of enhanced-potency IPV was performed. Studies reporting the clinical efficacy of IPV were also reviewed.Twenty study arms from 12 published articles were included in the analysis of seroconversion. One full dose of intramuscular IPV seroconverted 33%, 41%, and 47% of infants against serotypes 1, 2, and 3 on average, whereas 2 full doses seroconverted 79%, 80%, and 90%, respectively. Seroconversion increased with age at administration. Limited data from case-control studies indicate clinical efficacy equivalent to the proportion seroconverting. One fractional dose of intradermal IPV gave lower seroconversion (10%-40%), but after 2 doses seroconversion was comparable to that with full-dose IPV.Routine immunization with 2 full or fractional doses of IPV given after 10 weeks of age is likely to protect >80% of recipients against poliomyelitis if poliovirus reemerges after withdrawal of OPV serotypes.
Project description:In 2014, 2 studies showed that inactivated poliovirus vaccine (IPV) boosts intestinal immunity in children previously immunized with oral poliovirus vaccine (OPV). As a result, IPV was introduced in mass campaigns to help achieve polio eradication.We conducted an open-label, randomized, controlled trial to assess the duration of the boost in intestinal immunity following a dose of IPV given to OPV-immunized children. Nine hundred healthy children in Vellore, India, aged 1-4 years were randomized (1:1:1) to receive IPV at 5 months (arm A), at enrollment (arm B), or no vaccine (arm C). The primary outcome was poliovirus shedding in stool 7 days after bivalent OPV challenge at 11 months.For children in arms A, B, and C, 284 (94.7%), 297 (99.0%), and 296 (98.7%), respectively, were eligible for primary per-protocol analysis. Poliovirus shedding 7 days after challenge was less prevalent in arms A and B compared with C (24.6%, 25.6%, and 36.4%, respectively; risk ratio 0.68 [95% confidence interval: 0.53-0.87] for A versus C, and 0.70 [0.55-0.90] for B versus C).Protection against poliovirus remained elevated 6 and 11 months after an IPV boost, although at a lower level than reported at 1 month.CTRI/2014/09/004979.
Project description:Background:As wild poliovirus is eradicated and countries switch from oral poliovirus vaccine (OPV) to inactivated poliovirus vaccine (IPV) per World Health Organization recommendations, preventing circulation of vaccine-derived poliovirus (cVDPV) is a top priority. Currently, the impact of prior poliovirus vaccination on OPV shedding is not fully understood. Methods:Stool samples from 2 populations were tested for OPV to assess shedding patterns. 505 samples from 43 US children vaccinated with OPV were collected over 42 days post-vaccination. 1,379 samples from 148 Mexican children vaccinated with OPV were collected over 71 days post-vaccination. Prior vaccination history was recorded for both groups. Results:Seventeen (40%) of the US children had never received poliovirus vaccination while the Mexican children had received at least 2 doses of IPV and 116 (78%) had OPV exposure. In total, 84% of US children and 78% of Mexican children shed OPV (P = .44, Fisher exact test), with a mean shedding duration of 17.4 days for US children and 9.3 days for Mexican children (P < .0001, Wilcoxon-Mann Whitney test). Conclusions:Prior vaccination did not affect the likelihood of shedding, as the US and Mexico cohorts had similar shedding proportions. However, prior vaccination affected shedding duration as the Mexican children, who were largely OPV exposed and all of whom had at least 2 IPV vaccinations, shed OPV for half as long as the US cohort. Since different countries maintain different poliovirus vaccination schedules, it is likely that duration of shedding of OPV varies in populations around the world.
Project description:Background:Mutations associated with prolonged replication of the attenuated polioviruses found in oral poliovirus vaccine (OPV) can lead to vaccine-derived poliovirus (VDPV) and cause paralysis indistinguishable from that caused by wild poliovirus. In response, the World Health Organization has initiated the transition to exclusive use of inactivated poliovirus vaccine (IPV), with OPV administration in cases of outbreak. However, it is currently unclear how IPV-only vaccination, well known to provide humoral but not mucosal immunity, will impact the development of paralysis causing OPV variants. Children infected with human immunodeficiency virus (HIV) have been documented to show decreased mucosal immunity following OPV vaccination. Thus, HIV-infected children vaccinated with OPV may serve as proxy for children with IPV-only vaccination. Methods:We conducted a prospective study of Zimbabwean infants receiving OPV as part of their routine vaccination schedule. Stool samples collected from OPV-vaccinated children serially until age 24 months were tested for OPV serotypes using a real-time polymerase chain reaction protocol that quantifies the amount of mutant OPV variants found in each sample. Results:Out of 2130 stool samples collected from 402 infants 365 stool samples were OPV positive: 313 from 212 HIV-noninfected (HIV-) infants and 52 from 34 HIV-infected (HIV+) infants. HIV- infants showed significantly higher proportions of OPV mutants when compared to HIV+ infants. Conclusions:HIV infection is associated with a reduced proportion of OPV vaccine associated paralytic polio mutants. These results suggest that OPV administered to individuals previously vaccinated only with IPV will show decreased propensity for OPV mutations.