The effect of increased inoculum on oral rotavirus vaccine take among infants in Dhaka, Bangladesh: A double-blind, parallel group, randomized, controlled trial

Abstract

Background: Oral, live-attenuated rotavirus vaccines suffer from impaired immunogenicity and efficacy in low-income countries. Increasing the inoculum of vaccine might improve vaccine response, but this approach has been inadequately explored in low-income countries.

Methods: We performed a double-blind, parallel group, randomized controlled trial from June 2017 through June 2018 in the urban Mirpur slum of Dhaka, Bangladesh to compare vaccine take (primary outcome) among healthy infants randomized to receive either the standard dose or double the standard dose of oral Rotarix (GlaxoSmithKline) vaccine at 6 and 10 weeks of life. Infants with congenital malformations, birth or enrollment weight <2000 gm, known immunocompromising condition, enrollment in another vaccine trial, or other household member enrolled in the study were excluded. Infants were randomized using random permuted blocks. Vaccine take was defined as detection of post-vaccination fecal vaccine shedding by real-time reverse transcription polymerase chain reaction with sequence confirmation or plasma rotavirus-specific immunoglobulin A (RV-IgA) seroconversion 4 weeks following the second dose.

Results: 220 infants were enrolled and randomized (110 per group). 97 standard-dose and 92 high-dose infants completed the study per-protocol. For the primary outcome, no significant difference was observed between groups: vaccine take occurred in 62 (67%) high-dose infants versus 69 (71%) standard-dose infants (RR 0.92, 95% CI 0.67-1.24). However, in post-hoc analysis, children with confirmed vaccine replication had significantly increased RV-IgA responses, independent of the intervention. No significant adverse events related to study participation were detected.

Conclusions: Administration of double the standard dose of an oral, live-attenuated rotavirus vaccine (Rotarix) did not improve vaccine take among infants in urban Dhaka, Bangladesh. However, improved immunogenicity in children with vaccine replication irrespective of initial inoculum provides further evidence for the need to promote in-host replication and improved gut health to improve oral vaccine response in low-income settings. ClinicalTrials.gov: NCT02992197.

Keywords: Immunogenicity; Oral vaccine; Rotavirus; Vaccine shedding; Vaccine take; Vaccine underperformance.

Conflict of interest statement

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Monica McNeal has Laboratory Service agreements with Merck. All other authors have no competing interests to declare.].

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Fig. 1.

CONSORT diagram of participant flow. (1). Child in standard-dose arm withdrawn due to subacute intestinal obstruction that occurred before the child was scheduled to receive the first vaccine dose. Child in high-dose arm withdrawn due to diagnosis of a previously undetected congenital diaphragmatic hernia during hospitalization for pneumonia after the first vaccine dose. (2). Child in standard-dose arm received Rotarix outside the study; child in high-dose arm had been enrolled in a polio vaccine trial.

Fig. 2.

Summary of safety data for solicited AEs occurring within seven days post-vaccination. Data represent percentage of children with each solicited AE with associated standard error. No significant differences in any solicited AE occurring during the seven days following either vaccine dose were observed in the high-dose arm compared to the low-dose arm. Pre-vaccination and unsolicited AE data are not represented. All P values >0.300 unless otherwise indicated. *P = 0.138.

Fig 3.

Frequency of seroconversion, sequenced-confirmed fecal Rotarix vaccine shedding, and overall vaccine take by study arm. Data represent percentage of children achieving each outcome with associated standard error. No significant difference in any outcome was detected between groups (P > 0.300).

Fig 4.

Kinetics of sequence-confirmed Rotarix vaccine virus shedding post-vaccination. Mean Cq values and standard error of the mean (SEM) are depicted. (A): Mean Cq values of all evaluable stool specimens from all participants at each post-vaccination time point are shown. No significant differences were observed between arms in mean Cq at any time point. (B): Rotarix-strain virus replication was confirmed by detection of decreased Cq value (i.e. higher stool viral burden) 6–7 days compared to 3–4 days following either dose 1 (N = 65 participants) or dose 2 (N = 31 participants), or at 2 weeks compared to either 3–4 or 6–7 days following either dose 1 or dose 2. Curves for post-dose 1 and post-dose 2 shedding are depicted on the same plot for presentation but represent distinct analyses. No significant differences were observed between arms in mean Cq at any time point.