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A Randomized, Controlled Trial of the Impact of Alternative Dosing Schedules on the Immune Response to Human Rotavirus Vaccine in Rural Ghanaian Infants

Sunday, 22nd of May 2016

The Journal of Infectious Diseases

Volume 213, Issue 11

Pp. 1678-1685.

J Infect Dis. (2016) 213 (11): 1678-1685. doi: 10.1093/infdis/jiw023 First published online: January 27, 2016

A Randomized, Controlled Trial of the Impact of Alternative Dosing Schedules on the Immune Response to Human Rotavirus Vaccine in Rural Ghanaian Infants

George Armah1,

Kristen D. C. Lewis4,a,

Margaret M. Cortese5,

Umesh D. Parashar5,

Akosua Ansah2,

Lauren Gazley4,a,

John C. Victor4,

Monica M. McNeal6,

Fred Binka3 and

A. Duncan Steele4,a

- Author Affiliations

1Noguchi Memorial Institute for Medical Research, University of Ghana, Legon

2Navrongo Health Research Centre

3University of Health and Allied Health Services, Ho, Ghana

4PATH, Seattle, Washington

5Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia

6Department of Pediatrics, Division of Infectious Diseases, Cincinnati Childrens Hospital Medical Center, Ohio

Correspondence: K. D. C. Lewis, PO Box 23350, Seattle, WA 98102-0650 (kristen.lewis@gatesfoundation.org).

Presented in part: Vaccines for Enteric Diseases Conference, Bangkok, Thailand, 6–8 November 2013; African Rotavirus Symposium, Livingstone, Zambia, 12–13 June 2014.

↵a Present affiliations: Pneumonia Global Health Program (K. D. C. L.) and Enteric and Diarrheal Diseases Global Health Program (A. D. S.), Bill & Melinda Gates Foundation, Seattle, Washington; and Trillium Community Health Plan, Eugene, Oregon (L. G.).

 

Excerpts below; full text is at http://jid.oxfordjournals.org/content/213/11/1678.full

 Abstract

Background. The recommended schedule for receipt of 2-dose human rotavirus vaccine (HRV) coincides with receipt of the first and second doses of diphtheria, pertussis, and tetanus vaccine (ie, 6 and 10 weeks of age, respectively). Alternative schedules and additional doses of HRV have been proposed and may improve vaccine performance in low-income countries.

Methods. In this randomized trial in rural Ghana, HRV was administered at ages 6 and 10 weeks (group 1), 10 and 14 weeks (group 2), or 6, 10, and 14 weeks (group 3). We compared serum antirotavirus immunoglobulin A (IgA) seroconversion (≥20 U/mL) and geometric mean concentrations (GMCs) between group 1 and groups 2 and 3.

Results. Ninety-three percent of participants (424 of 456) completed the study per protocol. In groups 1, 2, and 3, the IgA seroconversion frequencies among participants with IgA levels of <20 U/mL at baseline were 28.9%, 37.4%, and 43.4%, respectively (group 1 vs group 3, P = .014; group 1 vs group 2, P = .163). Postvaccination IgA GMCs were 22.1 U/mL, 26.5 U/mL, and 32.6 U/mL in groups 1, 2, and 3, respectively (group 1 vs group 3, P = .038; group 1 vs group 2, P = .304).

Conclusions. A third dose of HRV resulted in increased seroconversion frequencies and GMCs, compared with 2 doses administered at 6 and 10 weeks of age. Since there is no correlate of protection, a postmarketing effectiveness study is required to determine whether the improvement in immune response translates into a public health benefit in low-income countries.

Clinical Trials Registration. NCT015751.

(See the editorial commentary by Cunliffe and Kang on pages 1673–5, and major article by Zaman et al on pages 1686–93.)

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Rotavirus is a leading cause of diarrhea-associated mortality among children <5 years of age in low-income countries (LICs) [1, 2], with countries in sub-Saharan Africa exhibiting the highest rates of rotavirus-associated mortality [2]. In Ghana, rotavirus is a common cause of diarrhea, circulating from approximately September/October to February/March [3–6]. Prior to widespread introduction of rotavirus vaccine, rotavirus was responsible for approximately 50% of diarrheal hospitalizations among children aged <5 years [7].

Two orally administered human rotavirus vaccines (HRVs), Rotarix (GSK Biologicals, Rixensart, Belgium) and RotaTeq (Merck, West Point, Pennsylvania), are recommended by the World Health Organization (WHO) for inclusion in the infant immunization series. While antirotavirus immunoglobulin A (IgA) seroconversion frequencies with these vaccines range between approximately 87% and 95% in high-income countries (HICs) [8, 9], rates in Africa and Asia have been consistently lower, between 36% and 78% [3, 10–12]. Similarly, IgA geometric mean concentrations (GMCs) in LICs are approximately 5–10 times lower than those in HICs [3], and, while vaccine efficacy against severe rotavirus diarrhea in HICs is high [8, 13], there is moderate efficacy among children in LICs [10, 14–16].

The reasons postulated for the observed reduced response to rotavirus vaccines in LICs include the presence of high maternal antirotavirus antibody titers, interference by the first dose of coadministered oral polio vaccine (OPV), altered gut microbiota, enteropathy, and malnutrition [17–20]. In LICs, HRV is administered in a 2-dose schedule at 6 and 10 weeks of age (WHO Expanded Programme on Immunization [EPI] visits 1 and 2). Pragmatic ways to overcome the effect of some of these factors might be to administer a third dose at 14 weeks of age (EPI visit 3) or, although not considered practical in maximizing EPI coverage, delay administration of the standard 2-dose schedule to a slightly older age, when maternal antibody levels have declined and when there is lower risk of interference from concomitant administration with the first OPV dose.

Previous studies assessed whether alternate schedules improve vaccine responses in infants from LICs. One study evaluated the immunogenicity and efficacy of HRV through 2 years of age in South Africa and Malawi, finding consistent trends indicating that a 3-dose HRV schedule (6, 10, and 14 weeks of age) may be optimal as compared to a 2-dose schedule administered at an older age (10 and 14 weeks of age) [21]. In an earlier South African immunogenicity study, infants receiving 2 doses of a lower-dose HRV at 6 and 10 weeks of age had lower immune responses as compared to infants receiving 2 doses at 10 and 14 weeks of age [19]. Thus, the increases in immunogenicity and efficacy of a 3-dose schedule identified in the South Africa and Malawi study may be even more pronounced when compared to a 2-dose schedule given at an earlier recommended schedule (6 and 10 weeks of age).

To investigate whether a 3-dose schedule of HRV administered at 6, 10, and 14 weeks of age is superior to a 2-dose schedule in which vaccine is given at the recommended earlier ages (6 and 10 weeks of age), we conducted a phase 4, single-center, individually randomized, open-label trial in rural Ghana. Secondary objectives included assessing whether 2 doses of HRV administered at a delayed schedule of 10 and 14 weeks of age were superior to 2 doses administered at 6 and 10 weeks of age, comparing the effect of high versus low levels of maternally derived antirotavirus immunoglobulin G (IgG) on the immune response to vaccination, and describing vaccine-type rotavirus shedding.