Multi-scale assessment of rotavirus vaccination: determinants of immunological, clinical and population-level effects Open Access

Abstract

Starting in 2006, rotavirus vaccines have been integrated into 96 national immunization programs. Yet, rotavirus gastroenteritis continues to cause 128,500-215,000 deaths among children under 5 years of age annually. This research aimed to generate insights that will help mitigate two major challenges preventing global success of the rotavirus vaccine and to understand the population-level effects of vaccination.

 

Rotavirus vaccines are substantially less immunogenic in high child mortality settings when compared to low child mortality settings. In Aim 1, we assessed individual and country-level factors associated with rotavirus vaccine immunogenicity. We pooled individual-level data on vaccinated infants from 22 clinical trials conducted across child mortality settings. Using multilevel logistic regression, we found oral polio vaccination given concomitantly with the first two rotavirus vaccine doses reduced seroconversion by 37% (OR=0.63, 95% CI=0.47, 0.84). 

 

Given the need for improved rotavirus vaccine performance, a simple and effective method for evaluating new vaccination strategies and potential vaccine candidates is essential. In Aim 2, we assessed serum IgA as a correlate of protection for reduced risk of rotavirus gastroenteritis in high and low child mortality settings. Survival analysis methods were applied to follow-up data for vaccinated infants from pooled, individual-level clinical trial data. While no clear threshold indicating perfect protection across settings was identified, seroconversion served as a strong indicator of reduced risk of severe rotavirus gastroenteritis (child mortality setting: low: HR=0.04, 95% CI=0.01, 0.32; high: HR=0.48, 95% CI=0.26, 0.90). 

 

Aim 3 estimated the longer-term, population-wide impacts of rotavirus vaccination in the United States. Time series data on monthly rates of rotavirus gastroenteritis hospitalizations in the pre- and post-vaccine periods were analyzed using negative binomial logistic regression. Declines in rotavirus gastroenteritis and a shift from annual to biennial patterns were apparent across age groups. The results highlight the important role infants play in rotavirus transmission and the underappreciated burden in older populations. Overall, rotavirus gastroenteritis hospitalizations decreased by 69% (95% CI=62%, 76%).

 

Seroconversion is valuable for identifying drivers of differential vaccine immunogenicity and for predicting risk of rotavirus gastroenteritis. Introduction of the rotavirus vaccine can lead to altered longer-term patterns in rotavirus gastroenteritis across age groups.

This article has been accepted for publication in The Journal of Infectious Diseases. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. DOI: https://doi.org/10.1093/infdis/jiaa068 Link to article: https://academic.oup.com/jid/advance-article-abstract/doi/10.1093/infdis/jiaa068/5736407?redirectedFrom=fulltext

Table of Contents

1         Background   1

1.1      Child mortality and rotavirus burden of disease among young children       1

1.2      Rotavirus burden among older children and adults   2

1.3      Viral characteristics, transmission and infection       3

1.4      Rotavirus immunology           4

1.4.1   Mucosal and systemic immune response to rotavirus infection        4

1.4.2   Correlates of protection against rotavirus infection and rotavirus gastroenteritis     6

1.5      Seasonality of rotavirus gastroenteritis          8

1.6      Rotavirus vaccines     9

1.6.1   Vaccine safety 9

1.6.2   Currently available vaccines  9

1.6.3   Correlates of immunogenicity for rotavirus vaccines 13

1.7      Rotavirus vaccine challenges 14

1.7.1   Vaccine performance 14

1.7.2   Identification of a correlate of protection      17

1.8      Vaccine evaluation    18

1.9      Longer-term direct and indirect vaccine effects       22

2         Study rationale, specific aims and significance         23

2.1      Study rationale           23

2.2      Aims overview           25

3         Data sources   28

3.1      GSK clinical trials      28

3.2      Healthcare Cost and Utilization Project State Inpatient Database    36

3.3      National Center for Health Statistics Bridged Race data      37

3.4      MarketScan    38

4         Aim 1- Vaccine immunogenicity       41

5         Aim 2- Correlates of protection         75

6         Aim 3- Longer-term direct and indirect vaccine effects       108

7         Aim 3- Supplemental Study  133

8         Public Health Impact 163

8.1      Overview       163

8.2      Contribution of each specific aim      163

8.2.1   Aim 1- Immunogenicity        163

8.2.2   Aim 2- Correlates of protection         166

8.2.3   Aim 3- Direct and indirect vaccine effects   169

8.3      Summary        175

9         References     176

10       Appendix       210

About this Dissertation

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School	Laney Graduate School
Department	Epidemiology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Keyword	Gastroenteritis Rotavirus Immunogenicity Vaccine
Committee Chair / Thesis Advisor	Lopman, Benjamin A., Emory University
Committee Members	Leon, Juan, Emory University Haber, Michael J., Emory University Tate, Jacqueline E., Centers for Disease Control and Prevention

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