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Norovirus Infection and Vaccine Development

Miguel O’Ryan GProfessor

Facultad de MedicinaUniversidad de Chile

Chair N° 17 Chilean Academy of MedicineESCMID 2017

1972 1992ESCMID Online Lecture Library

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Conflict of Interest

Takeda Vaccines, Inc. research grant funding

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A myriad of pathogens

O’Ryan et al Exp Rev Anti infect ther 2010; 8: 671-681ESCMID 2017


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Norovirus

Caliciviridiae family• Norovirus• Sapovirus• Lagovirus• Vesivirus• Nebovirus

• Non-cultivatableESCMID 2017


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NorovirusClasificación

Genogroup II

Genogroup I

Genogroup III

Genogroup VI

Genogroup IV

Genogroup V

Bovine

Murine

Canine

Feline/Canine

Porcine

Ramani et al. Curr Opin GE 2014;30:25ESCMID 2017

Aprox 80% strains causing diseaseESCMID Online Lecture Library

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Impact of Disease

• Endemic gastroenteritis of childhood

• Gastroenteritis outbreaks compromising adults and children associated with food and/or water contamination

• Endemic gastroenteritis in adults• Gastroenteritis in the immune compromised host

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Norovirus Outbreaks• Schools• Restaurants• Summer camps• Resorts• Hospitals• Nursing homes• Cruise Ships• Battleships

USA: 50-60% food and waterborne outbreaks.

England: 43% food borne outbreaks.

Sweden and The Netherlands: 67% and 80% of outbreaks respectively.

Chile: 46% outbreaks

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One person hospitalizedOne person died!


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Other Special Populations

• Long term care facilities/hospitals

• Cruise ships/travelers

• Immunocompromised– Renal transplant patients

• MilitaryESCMID 2017


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Norovirus Outbreaks All age groups Vomiting, diarrhea, mild or no fever

Rapid onset (hours) after consumption of contaminated product First “wave” due to direct consumption tends to occur within 3 days Second “wave” due to person-person transmission can then last one or

more weeks. Duration of disease 2 to 8 days (mean about 4 days) Risk for dehydration in elderly, underlying disease

Impact?Loss of workMedical consultFew hospitalizations and deathsMainly in the elderly

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Impact of Disease

• Endemic gastroenteritis of childhood

• Gastroenteritis outbreaks compromising adults and children associated with food and/or water contamination

• Endemic gastroenteritis in adults• Gastroenteritis in the immune compromised host

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Impact of Rotavirus Vaccination:Norovirus the “new key player”

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United States

Finland

Payne D. N Eng J Med 2013; 368:1121-30Hemming M. Eur J Pediatr 2013; 172:739-746McAtee, Am. J Trop Med Hyg 2016;94:212Bucardi F. Plos One 2014;e98201


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Clinical Manifestations

• Watery diarrhea• Vomiting• Other symptoms – abd. cramps/pain, nausea, fever, headache

• Complications – Volume depletion– Hypokalemia– Malnutrition (immunocompromised)– DIC– Death

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The Burden of Norovirus

440,000 deaths

2 M hospitalized

25 M clinic visits

111 M episodes of gastroenteritis requiring only

home care

Rotavirusc

c worldwide children <5 yrs of ageParashar et al, EID, 2003

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Vaccine?• Reduction in diarrhea associated medical visits

– Depending on efficacy of vaccine could reduce:• Up to 15-20% of ER/Hospitalizations in children < 5

years of age• Up to 15% of ambulatory visits (similar to rotavirus)• Visits/Hospitalization/Deaths in adults/elder involved in

outbreaks?

• Reduction in diarrhea associated deaths– Estimated in up to 200.000 deaths per year

Vaccine priority: middle-high in children In special groups of adults: military, elderly, food

handlers?

Norovirus coadministered with rotavirus vaccine :

↓≈50-60% ADE‐hospitalization in children < 5 years of age↓≈ 45% ADE‐emergency room visits↓≈ 30% ADE‐ambulatory medical consults

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NorovirusClasificación

Genogroup II

Genogroup IPorcine

Ramani et al. Curr Opin GE 2014;30:25ESCMID 2017


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Can protection be achieved?“Natural infections over time”


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Virus‐like particles (VLPs)

• Live virus vaccine not possible…yet

• Protein capsids that self‐assemble and mimic the capsid structure.

• Not infectious‐lack viral genes (empty).

• Made in large amounts (22mg/300ml) and very stable. Can be lyophilized.

Vaccine induces serum HBGA blockingantibodies; anti-Norovirus IgAand IgG memory B cellsCortes-Penfield et al 2017, Ramani et al 2017

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Vaccines in advanced stage of development

• VLP based candidates

– Prototype: intranasal administration; monovalent GI.1

VLP

– IM bivalent GI.1 and GII.4 VLPs

• Includes Al(OH)3 (aluminum hydroxide) and MPL adjuvant

ESCMID 2017 Taminnen K et al Plos One July 2013


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An Intramuscular Bivalent Norovirus GI.1/GII.4 Virus Like Particle Vaccine Protects Acute Gastroenteritis after Experimental Human GII.4 Oral Challenge

David I. Bernstein MD, MA, Robert L. Atmar MD, G. Marshal Lyon MD, MMSc, John J. Treanor MD, Wilbur H. Chen MD, MS, Robert W Frenck MD, Xi Jiang PhD, Jan Vinjé PhD, Mohamed S. AL‐Ibrahim MD, Jill Barrett MPH, David Y. Graham MD, Charles Richardson PhD, Robert Goodwin PhD, Astrid Borkowski MD, PhD, Ralf Clemens MD, PhD, and Paul M. Mendelman MD

Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, Baylor College of Medicine and Michael E. DeBakey VAMC, Houston, TX, Emory University School of Medicine, Atlanta, GA, University of Rochester Medical Center, Rochester, NY University of Maryland School of Medicine, Baltimore, MD, Centers for Disease Control and Prevention, Atlanta, GA, Shin Nippon Biomedical Laboratories, Baltimore, MD, The EMMES Corp., Rockville, MD, Takeda Vaccines (Montana), Bozeman, MT, and Takeda Vaccines, Zurich, Switzerland

ID Week Presentation, San Francisco October 5, 2013ESCMID 2017


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0

1

2

3

4

5

Vomiting or Diarrhea

Vaccine(n=50)

Placebo(n=48)

Results: Severe AGE Symptoms

No. of Challenged Subjects with

Severe Symptoms

Gastroenteritis Symptom

Vaccine (%)

n = 50

Placebo (%)

n = 48

Rate Difference (95% CI)

% Reduction(95% CI)

p value (Fisher’s

Exact)Severe vomiting and/or diarrhea

0(0%)

4(8.3%)

‐8.3(‐16.2, ‐0.5)

100.0% (‐,‐)

0.054

• 100% reduction observed in severe vomiting and/or diarrhea in PCR+ subjects receiving vaccine vs placebo

Study LV03‐105

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0

2

4

6

8

10


Vaccine(n=50)

Placebo(n=48)

Results: Moderate or Severe AGE Symptoms

No. of Challenged Subjects with Moderate or

Severe Symptoms

Gastroenteritis SymptomVaccine

(%)n = 50

Placebo (%)

n = 48


% Reduction(95% CI)

p value (Fisher’s

Exact)

Moderate or severe vomiting AND/OR diarrhea

3(6.0%)

9(18.8%)

‐12.8(‐25.6, 0.1)

68.0%(‐11.2, 90.8) 0.068

• 68% reduction observed in moderate or severe vomiting and/or diarrhea in PCR+ subjects receiving vaccine vs placebo

Study LV03‐105

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0

5

10

15

20


Vaccine(n=50)

Placebo(n=48)

Results: Mild, Moderate or Severe AGE Symptoms

No. of Challenged Subjects with Mild, Moderate or Severe

Symptoms

Gastroenteritis SymptomVaccine

(%)n = 50

Placebo (%)

n = 48


% Reduction(95% CI)

p value (Fisher’s

Exact)Mild, moderate or severe vomiting and/or diarrhea

9(18.0)

18(37.5)

‐19.5 (‐36.8, ‐2.2)

52.0 (3.8, 76.1) 0.042

• 52% reduction observed in mild, moderate or severe vomiting and/or diarrhea in PCR+ subjects receiving vaccine vs placebo

Study LV03‐105

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CURRENT STATUS OF THE MOST ADVANCED VACCINE CANDIDATE

• A phase II trial including 454 adults randomly assigned to receive intramuscular saline placebo or vaccines containing either 15μg or 50μg of GI.1/ 50μg GII.4 VLPs was safe and showed a rapid immunogen response within 7‐10 days. (AtmarRL, Baehner F, Cramer JP, et al. J Infect Dis. 2016 15;214(6):845–53)

• Studies are currently underway to define the dose, adjuvants to be used in future phase IIb/III clinical trials and the response to the vaccine in children (NCT02153112, NCT02661490, 284 NCT02669121, NCT03039790).

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BUT..A VACCINE FOR WHOM?I) Food/waterborne gastroenteritis outbreaks affecting all ages• NoV accounts for 30-80% of outbreaks, and occurs in a variety of closed settings

including schools, day care centers, healthcare facilities, hotels, restaurants and shipsamong others

• Travelers, military

II) Acute endemic diarrhea in adults • NoV is a significant cause of acute endemic gastroenteritis in adults, accounting for 5-

15% of cases. Among adults, the elderly population is the most susceptible to severe infection which can be accompanied by severe dehydration requiring ICU admission and in some instances, death

• Elderly, care facilities

III) Acute endemic diarrhea in children• NoV is second to rotavirus as cause of cute endemic diarrhea in children in middle-high

income countries accounting for 10-20% of associated hospitalizations and emergency room visits, less clear in low resource countries where rates range from 1-15%. “New leader” in countries that have implemented rotavirus vaccines

• Infants together with rotavirus (VP6? or VP4 types?)/slightly older children?

IV) ImmunocompromisedIn bone marrow and solid organ transplant patients, NoV can cause more severe and/or

prolonged gastroenteritisESCMID 2017


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