Vaccine-induced mucosal immunity to poliovirus: analysis of cohorts from an open-label, randomised controlled trial in Latin American infants

Abstract

SummaryBackgroundIdentification of mechanisms that limit poliovirus replication is crucial for informing decisions aimed at global polio eradication. Studies of mucosal immunity induced by oral poliovirus (OPV) or inactivated poliovirus (IPV) vaccines and mixed schedules thereof will determine the effectiveness of different vaccine strategies to block virus shedding. We used samples from a clinical trial of different vaccination schedules to measure intestinal immunity as judged by neutralisation of virus and virus-specific IgA in stools.MethodsIn the FIDEC trial, Latin American infants were randomly assigned to nine groups to assess the efficacy of two schedules of bivalent OPV (bOPV) and IPV and challenge with monovalent type 2 OPV, and stools samples were collected. We selected three groups of particular interest—the bOPV control group (serotypes 1 and 3 at 6, 10, and 14 weeks), the trivalent attenuated OPV (tOPV) control group (tOPV at 6, 10, and 14 weeks), and the bOPV–IPV group (bOPV at 6, 10, and 14 weeks plus IPV at 14 weeks). Neutralising activity and poliovirus type-specific IgA were measured in stool after a monovalent OPV type 2 challenge at 18 weeks of age. Mucosal immunity was measured by in-vitro neutralisation of a type 2 polio pseudovirus (PV2). Neutralisation titres and total and poliovirus-type-specific IgG and IgA concentrations in stools were assessed in samples collected before challenge and 2 weeks after challenge from all participants.Findings210 infants from Guatemala and Dominican Republic were included in this analysis. Of 38 infants tested for mucosal antibody in the tOPV group, two were shedding virus 1 week after challenge, compared with 59 of 85 infants receiving bOPV (p<0·0001) and 53 of 87 infants receiving bOPV–IPV (p<0·0001). Mucosal type 2 neutralisation and type-specific IgA were noted primarily in response to tOPV. An inverse correlation was noted between virus shedding and both serum type 2 neutralisation at challenge (p<0·0001) and mucosal type 2 neutralisation at challenge (p<0·0001).InterpretationMucosal type-2-specific antibodies can be measured in stool and develop in response to receipt of OPV type 2 either in the primary vaccine series or at challenge. These mucosal antibodies influence the amount of virus that is shed in an established infection.FundingBill & Melinda Gates Foundation.

Maximising the impact of inactivated polio vaccines

“…By contrast, the intestinal immunity induced by live, oral vaccines is close to achieving the ideal of sterilising immunity. 10–12 Ultimately, blocking transmission (e.g., via integrated OPV-IPV intestinal immune boosting strategies 13,14 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.…”

Intestinal antibody responses to a live oral poliovirus vaccine challenge among adults previously immunized with inactivated polio vaccine in Sweden

“…Specifically, infants with detectable viral shedding following mOPV2 challenge exhibited brisk intestinal antibody responses, with significant increases in poliovirus type 2-specific stool IgA and neutralising activity titers by 2 weeks’ postchallenge. Parallel rises in poliovirus type 2-specific mucosal immune markers following mOPV2 challenge have also been reported among infants from Guatemala and the Dominican Republic who received a primary immunisation series of three doses of bivalent OPV (ie, targeting poliovirus types 1 and 3) plus one dose of IPV 10…”

“…The observation that, despite documented viral replication and sustained excretion, the Swedish study participants failed to mount an intestinal antibody response to mOPV1 challenge was unanticipated and in marked contrast to the experiences of five OPV challenge studies in paediatric participants 10–12 15 29. For both of the aforementioned mOPV1 challenge studies in the USA29 and Oman,15 rises in poliovirus type 1-specific intestinal immune markers (ie, IgA in stool specimens and neutralising activity, respectively) were reported in the IPV recipients following mOPV1 receipt.…”

“…Stool samples collected from the study participants and stored frozen at the National Institute for Public Health and the Environment (Bilthoven, The Netherlands) were identified, thawed, aliquoted and refrozen prior to shipping to the USA 10 11 15 25. This excluded any possibility of chloroform treatment, which is used in virus titration but has been previously shown to inactivate antibody activity (Wright laboratory, unpublished data).…”

“…Today, >50 years of scientific research confirm that live-attenuated oral polio vaccines (OPVs) administered in childhood are capable of stimulating the production of poliovirus-specific neutralising antibodies in nasopharyngeal and gastrointestinal mucosal tissues9–12 and thereby inhibiting poliovirus replication on subsequent homologous OPV challenge 13–15. In contrast, current evidence suggests childhood immunisation schedules based exclusively on inactivated (killed) polio vaccines (IPVs) induce only negligible intestinal immunity3 9 11 16 and fail to interrupt viral replication on subsequent exposure to either vaccine virus14 17 18 or circulating wild-type viruses 19–21…”