Anticipating Challenges to Norovirus Vaccines: Modeling Analyses to Understand How Norovirus Transmission and Genetic Diversity Could Affect Vaccine Development and Implementation Open Access

Steele, Molly (Summer 2019)

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Noroviruses are among the leading causes of diarrheal disease worldwide. Norovirus vaccines are currently in development; however there are several characteristics of norovirus that are not well understood and could hamper vaccine development and implementation.

In Aim 1, we estimated how norovirus transmission varies between age groups and how this variability could affect vaccine implementation. Using a deterministic, age-structured model of transmission and vaccination, we found that children under 5 years old contributed the most to transmission (age-specific basic reproduction number (R0) of 4.3). Thus pediatric vaccination was predicted to avert 18-21 times more cases and twice as many deaths per vaccinee compared to elderly vaccination.

The size and severity of norovirus outbreaks varies across different settings, times of year and for different genotypes, suggesting that norovirus transmission is variable at the scale of outbreaks. In Aim 2, we estimated the basic (R0) and effective (Re) reproduction numbers for norovirus outbreaks in the US and used regression models to assess whether factors such as setting and season were associated with transmissibility. We found that norovirus outbreaks in the US have modest values of R0 and Re (2.75 [IQR: 2.38, 3.65] and 1.29 [IQR: 1.12, 1.74], respectively) and that outbreaks had higher transmission within long-term care/assisted living facilities, during winter, and when norovirus was the confirmed etiology.

GII.4 noroviruses evolve rapidly, and the extent of cross-immunity between strains is poorly understood. In Aim 3, we quantified the level of cross-immunity between multiple GII.4 strains. We developed a set of coupled single-strain models to estimate changes in population-level susceptibility and calculate the level of cross-immunity between strains. We estimated that the level of cross-immunity between Farmington Hill to Hunter and Hunter to Den Haag was high (0.84 - 0.91 and 0.91 - 0.94, respectively) and low between New Orleans to Sydney (0.34 – 0.73).

The variability of transmission both at the population-level and at the level of outbreaks provides key insights into which populations to target for vaccination. Certain GII.4 strains are associated with high cross-immunity, indicating vaccine formulations containing these strains may provide cross-protection against future strains of GII.4 norovirus.

Table of Contents

1    Introduction. 1

  1.1  Global mortality and the burden of norovirus. 1

  1.2  Burden of norovirus in the United States. 2

  1.3  Norovirus seasonality. 2

  1.4  Viral characterization. 3

  1.5  Evolution of Noroviruses. 3

  1.6  Natural history and transmission of norovirus. 4

  1.7  Host susceptibility and immunity. 6

  1.8  Norovirus in outbreak settings. 8

  1.9  Norovirus vaccines. 8

  1.10 Challenges that norovirus poses to vaccine development and implementation. 9

  1.11 The value of dynamic models for studying infectious disease epidemiology. 12

2    Significance. 15

  2.1  Aim 1 Rationale and Overview.. 15

  2.2  Aim 2 Rationale and Overview.. 17

  2.3  Aim 3 Rationale and Overview.. 18

3    Manuscript for Aim 1. 20

4    Manuscript for Aim 2. 58

5    Manuscript for Aim 3. 85

6    Conclusion. 121

  6.1  Contribution of Aim 1. 121

  6.2  Contribution of Aim 2. 124

  6.3  Contribution of Aim 3. 126

6.3.1      Comparison of GII.4 norovirus datasets. 127

6.3.2      Comparison of multi-strain models. 128

6.3.3      Estimates of susceptibility to and cross-immunity between GII.4 norovirus strains. 129

  6.4  Summary. 131

7    References. 132

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