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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

Saturday, 23rd of August 2014

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

Dear All,

A place for IPV in interrupting WPV in the remaining endemic countries?

See also the commentary by Kimberly Thompson in the same issue, at

 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)60983-1/fulltext

Good reading, BD 

The Lancet, Early Online Publication, 11 July 2014

Copyright © 2014 Elsevier Ltd All rights reserved.

Jacob John MD a *, Sidhartha Giri MD a *, Arun S Karthikeyan MSc a, Miren Iturriza-Gomara PhD a b, Prof Jayaprakash Muliyil DrPH a, Prof Asha Abraham PhD a, Prof Nicholas C Grassly DPhil a c †, Prof Gagandeep Kang PhD a †

Summary and introduction below; full text, with figures, is at http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960934-X/fulltext

Background

Intestinal immunity induced by oral poliovirus vaccine (OPV) is imperfect and wanes with time, permitting transmission of infection by immunised children. Inactivated poliovirus vaccine (IPV) does not induce an intestinal mucosal immune response, but could boost protection in children who are mucosally primed through previous exposure to OPV. We aimed to assess the effect of IPV on intestinal immunity in children previously vaccinated with OPV.

Methods

We did an open-label, randomised controlled trial in children aged 1—4 years from Chinnallapuram, Vellore, India, who were healthy, had not received IPV before, and had had their last dose of OPV at least 6 months before enrolment. Children were randomly assigned (1:1) to receive 0·5 mL IPV intramuscularly (containing 40, 8, and 32 D antigen units for serotypes 1, 2, and 3) or no vaccine. The randomisation sequence was computer generated with a blocked randomisation procedure with block sizes of ten by an independent statistician. The laboratory staff did blinded assessments. The primary outcome was the proportion of children shedding poliovirus 7 days after a challenge dose of serotype 1 and 3 bivalent OPV (bOPV). A second dose of bOPV was given to children in the no vaccine group to assess intestinal immunity resulting from the first dose. A per-protocol analysis was planned for all children who provided a stool sample at 7 days after bOPV challenge. This trial is registered with Clinical Trials Registry of India, number CTRI/2012/09/003005.

Findings

Between Aug 19, 2013, and Sept 13, 2013, 450 children were enrolled and randomly assigned into study groups. 225 children received IPV and 225 no vaccine. 222 children in the no vaccine group and 224 children in the IPV group had stool samples available for primary analysis 7 days after bOPV challenge. In the IPV group, 27 (12%) children shed serotype 1 poliovirus and 17 (8%) shed serotype 3 poliovirus compared with 43 (19%) and 57 (26%) in the no vaccine group (risk ratio 0·62, 95% CI 0·40—0·97, p=0·0375; 0·30, 0·18—0·49, p<0·0001). No adverse events were related to the study interventions.

Interpretation

The substantial boost in intestinal immunity conferred by a supplementary dose of IPV given to children younger than 5 years who had previously received OPV shows a potential role for this vaccine in immunisation activities to accelerate eradication and prevent outbreaks of poliomyelitis.

Funding

Bill & Melinda Gates Foundation.

Introduction

The Global Polio Eradication Initiative (GPEI) has relied on oral poliovirus vaccine (OPV) to successfully eliminate wild poliovirus transmission from most of the world. However, three countries remain persistently infected with indigenous poliovirus (Afghanistan, Pakistan, and Nigeria), and export of virus has led to large outbreaks in Africa, Asia, and Europe in the past decade. Response to these outbreaks and elimination of transmission in the remaining reservoirs are major challenges for the GPEI.1

OPV has been the vaccine of choice for the GPEI because of its ease of administration in mass campaigns, low cost, and ability to induce strong intestinal mucosal immunity against poliovirus shedding and transmission. However, poor immunogenicity of OPV in areas with poor sanitation and hygiene has restricted its effectiveness in the prevention of transmission.2 Additionally, intestinal mucosal immunity induced by OPV wanes substantially within a year of vaccination.3 Therefore, although children and adults vaccinated with OPV are protected against poliomyelitis if they mount a neutralising antibody response to all three serotypes they might still be susceptible to infection and transmit wild poliovirus.4, 5 Infected adults have been implicated in international spread and outbreaks of poliomyelitis, and incomplete intestinal immunity in OPV-vaccinated individuals might contribute to persistent transmission in infected areas.6, 7

The injected inactivated poliovirus vaccine (IPV) has excellent immunogenicity that does not vary between populations.8 However, it does not induce an effective mucosal immune response—poliovirus-specific IgA is undetectable in serum or saliva in most children after administration of IPV9, 10—and offers restricted protection against poliovirus shedding in the intestine after challenge with OPV, most likely explained by transudated serum IgG.11 The effect of IPV on transmission of poliovirus, particularly in areas with efficient faecal—oral transmission is therefore likely to be limited compared with OPV.12 This view is supported by the recent widespread silent circulation of wild poliovirus in Israel, where routine immunisation with IPV replaced a combined IPV/OPV schedule in 2005, and where virus was detected in stool from children vaccinated with IPV but not associated with poliomyelitis.13

The administration of IPV with OPV during routine immunisation of infants did not reduce poliovirus shedding in stool after subsequent challenge with OPV when compared with infants immunised with OPV alone.14—16 However, adults who received OPV as children show increases in poliovirus-specific IgA and memory CD4+ T cells expressing the gut-homing integrin α4β7 after administration of IPV.9, 17 This finding suggests that IPV might boost intestinal immunity in children and adults who have been mucosally primed through earlier exposure to live poliovirus (vaccine or wildtype) and therefore have poliovirus-specific memory lymphocytes with a gut-homing phenotype, but whose intestinal immunity has waned. If so, IPV could be used as a complement to OPV in several ways: to prevent international spread by boosting intestinal immunity among travellers, to accelerate eradication in infected areas with poor OPV immunogenicity through use in campaigns, and to maximise herd immunity in advance of the planned global withdrawal of serotype 2 OPV in 2016.

Several countries have implemented routine infant immunisation schedules with IPV followed by OPV, which is associated with a strong humoral and mucosal immune response.15, 18 However, few studies have examined the results of immunisation with IPV in children previously vaccinated with OPV.19—21 These studies show a significant boost to serum antibodies, but only one study21 examined intestinal immunity. In this study, low poliovirus shedding was identified in stool after challenge at 15 months of age with serotype 3 monovalent OPV (13%), with no statistically significant difference between study groups receiving a supplemental dose of IPV or OPV at 9 months of age.21 Because of the paucity of data for the effect of IPV on intestinal immunity and the absence of studies of IPV given to OPV-immunised children older than 12 months whose immunity might have waned, we aimed to assess the effect of IPV on both systemic and intestinal mucosal immunity in Indian children aged 1—4 years who had received OPV at least 6 months previously.