Intestinal Immunity to Poliovirus Following Sequential Trivalent Inactivated Polio Vaccine/Bivalent Oral Polio Vaccine and Trivalent Inactivated Polio Vaccine-only Immunization Schedules: Analysis of an Open-label, Randomized, Controlled Trial in Chilean Infants

Abstract

Background: Identifying polio vaccine regimens that can elicit robust intestinal mucosal immunity and interrupt viral transmission is a key priority of the polio endgame.

Methods: In a 2013 Chilean clinical trial (NCT01841671) of trivalent inactivated polio vaccine (IPV) and bivalent oral polio vaccine (bOPV; targeting types 1 and 3), infants were randomized to receive IPV-bOPV-bOPV, IPV-IPV-bOPV, or IPV-IPV-IPV at 8, 16, and 24 weeks of age and challenged with monovalent oral polio vaccine type 2 (mOPV2) at 28 weeks. Using fecal samples collected from 152 participants, we investigated the extent to which IPV-bOPV and IPV-only immunization schedules induced intestinal neutralizing activity and immunoglobulin A against polio types 1 and 2.

Results: Overall, 37% of infants in the IPV-bOPV groups and 26% in the IPV-only arm had detectable type 2-specific stool neutralization after the primary vaccine series. In contrast, 1 challenge dose of mOPV2 induced brisk intestinal immune responses in all vaccine groups, and significant rises in type 2-specific stool neutralization titers (P < .0001) and immunoglobulin A concentrations (P < 0.0001) were measured 2 weeks after the challenge. In subsidiary analyses, duration of breastfeeding also appeared to be associated with the magnitude of polio-specific mucosal immune parameters measured in infant fecal samples.

Conclusions: Taken together, these results underscore the concept that mucosal and systemic immune responses to polio are separate in their induction, functionality, and potential impacts on transmission and, specifically, provide evidence that primary vaccine regimens lacking homologous live vaccine components are likely to induce only modest, type-specific intestinal immunity.

Figure 1.

Flow diagram for the selection of the analytical cohort from NCT 01841671, an investigation of the “Immunogenicity of 1 or 2 Doses of bOPV in Chilean Infants Primed with IPV Vaccine (IPV002ABMG),” undertaken in Santiago, Chile, between 25 April and 1 August 2013. Abbreviations: bOPV, bivalent oral polio vaccine; IgA, immunoglobulin A; IPV, trivalent inactivated polio vaccine; neut., neutralization. ^aReasons for exclusion are not mutually exclusive. ^bSubjects with missing type 2 oral poliovirus vaccine shedding data from at least 1 visit at 28, 29, 30, 31, or 32 weeks of age. ^cSubjects with missing polio type 2–specific stool neutralization and immunoglobulin A data from at least 1 visit at 28 or 30 weeks of age. ^dPolio type 1–specific immunoglobulin A data were missing from the visit at 30 weeks of age in 2 of the included subjects in the IPV-IPV-bOPV group and 1 in the IPV-IPV-IPV group. ^eType 1– and 2–specific serum neutralization data were missing from the visits at 28 and/or 29 weeks of age in 1 of the included subjects in the IPV-IPV-bOPV group and 3 in the IPV-bOPV-bOPV group.

Figure 2.

Systemic and intestinal immunity to polio types 1 and 2 at the time of the monovalent oral polio vaccine type 2 challenge (28 weeks of age) in infants previously immunized with IPV-bOPV-bOPV (n = 48), IPV-IPV-bOPV (n = 54), and IPV-IPV-IPV (n = 50). (A) Serum neutralization specific to poliovirus types 1 (P = .0001) and 2 (P = .0001), (B) stool neutralization specific to poliovirus types 1 (P = .0001) and 2 (P = .06), and (C) stool immunoglobulin A specific to poliovirus types 1 (P = .0001) and 2 (P = .004). Overall P values are from Kruskal-Wallis tests comparing the distributions of immune markers by primary vaccine group assignment; pairwise P values are from post hoc Dunn’s tests with Bonferroni correction for multiple testing within each grouping. Horizontal black bars indicate the median levels. Abbreviations: bOPV, bivalent oral polio vaccine; IgA, immunoglobulin A; IPV, trivalent inactivated polio vaccine; mOPV2, monovalent oral polio vaccine type 2.

Figure 3.

Polio type 2–specific intestinal immune responses to mOPV2 challenge in a random subgroup of infants (n = 20). (A) mOPV2 shedding, (B) type 2–specific stool neutralization, and (C) type 2–specific stool immunoglobulin A. Blue, circle-shaped markers indicate infants immunized with IPV-bOPV-bOPV (n = 7); orange, triangle-shaped markers indicate infants immunized with IPV-IPV-bOPV (n = 7); and red, square-shaped markers indicate infants immunized with IPV-IPV-IPV (n = 6). Abbreviations: bOPV, bivalent oral polio vaccine; IgA, immunoglobulin A; IPV, trivalent inactivated polio vaccine; mOPV2, monovalent oral polio vaccine type 2.

Figure 4.

Pairwise correlations between type 2–specific stool neutralization, immunoglobulin A, and mOPV shedding 2 weeks after mOPV2 challenge (ie, 30 weeks of age). Abbreviations: bOPV, bivalent oral polio vaccine; IgA, immunoglobulin A; IPV, trivalent inactivated polio vaccine; mOPV2, monovalent oral polio vaccine type 2.

Figure 5.

Intestinal immunity to polio type 2 at the time of and 2 weeks after monovalent oral polio vaccine type 2 challenge (ie, 28 and 30 weeks of age) by reported duration of breastfeeding. P values are from Mann-Whitney U tests comparing the distributions of immune markers by breastfeeding category. Horizontal black bars indicate the median levels. Blue, circle-shaped markers indicate infants immunized with IPV-bOPV-bOPV (n = 48); orange, triangle-shaped markers indicate infants immunized with IPV-IPV-bOPV (n = 54); and red, square-shaped markers indicate infants immunized with IPV-IPV-IPV (n = 50). Abbreviations: bOPV, bivalent oral polio vaccine; IgA, immunoglobulin A; IPV, trivalent inactivated polio vaccine; mOPV2, monovalent oral polio vaccine type 2.