Fecal shedding of rotavirus vaccine in premature babies in the neonatal unit

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1 Fecal shedding of rotavirus vaccine in premature babies in the neonatal unit Dr. Manish Sadarangani Director, Vaccine Evaluation Center, BC Children s Hospital Research Institute Assistant Professor, Division of Infectious Diseases, UBC Department of Pediatrics 6 December, 2016

2 Disclosure Statement Disclosure of Relationship I am a member of an Advisory Board or equivalent with a commercial organization. I am a member of a Speaker Bureau. I have received payment from a commercial organization (including gifts or other consideration or in kind compensation). I have received a grant(s) or an honorarium from a commercial organization. I hold a patent for a product referred to in the CME/CPD program or that is marketing by a commercial organization Company/Organization Pfizer I hold investments in a pharmaceutical organization, medical devices company or communications firms. I am currently participating in or have participated in a clinical trial within the past two years.).

3 Rotavirus infection Leading cause of severe childhood gastroenteritis - Vomiting, diarrhoea, abdominal pain +/- fever - Electrolyte imbalance - Dehydration + shock - Encephalitis, encephalopathy, cerebellitis - Death Per year globally - 25 million clinic visits, 2 million hospital admissions - 453,000 deaths in children <5y before rotavirus (RV) vaccine - 37% of diarrhea-related deaths, 5% of all deaths worldwide - 215,000 deaths since vaccine introducion

4 Rotavirus mortality under-5s Tate et al. Lancet Inf Dis (2012)

5 Rotavirus Vaccines Rotarix (RV1) - Attenuated human strain, G1P[8] - Protects against most disease strains Rotateq (RV5) - 5 bovine-human reassortants - G1, G2, G3, G4, P[8] VP7 G type, VP4 P type Angel et al. Nat Rev Micro (2007)

6 RV vaccines have been very successful 71% decrease in RV gastroenteritis hospitalizations 43% decrease in all gastroenteritis hospitalizations Wilson et al. PLoS One (2016) Gosselin et al. Can J Pub Health (2016)

7 Recommended schedule RV1 (UK) Immunisation against infectious disease (The Green Book) hcp.gsk.co.uk

8 Issues for premature babies Higher risk of severe disease if infected Minimal/no protection from maternal antibody - No placental IgG transfer <28 weeks gestation - Reduced feeding with breast milk Risk of healthcare-acquired infection Still in hospital in vaccine window period - Concerns about vaccine virus transmission to others

9 Study objectives Primary objective - Establish duration of excretion of RV1 vaccine in premature babies after immunization Secondary objectives - Collect data on adverse events of RV1 vaccine in premature babies - Assess if premature babies develop an effective immune response to RV1 vaccine - To collect samples for future analysis of microbiota on vaccine responses

10 Study population Neonatal unit inpatient (Oxford, UK) Receiving RV1 vaccine during admission Born at <37 weeks gestation January 2015 March 2016

11 Methods Fecal sample collection - Before RV1 immunization; Daily for up to 21 days after RV1 immunization - Stored in RNAlater RV1 detection - Viral RNA extracted using QIAamp viral RNA Mini kit - Quantitative reverse-transcriptase PCR amplification of NSP3 gene Gautam et al. PeerJ (2016)

12 Results Participant demographics Number of participants 17 Location High dependency unit 10 (59%) Low dependency unit 7 (41%) Birth gestational age Median 26.4 weeks Range 24.0 to 29.6 weeks Age at immunization Median 9.4 weeks Range 7.4 to 12.9 weeks Weight at immunization Median 2.33 kg Range 1.46 to 3.45 kg

13 Results PCR detection of RV1 # D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11 D12 D13 D14 D15 D16 D17 D18 D19 D20 D21 Days % shed pos % % % % % % % % % % Median 13 samples per participant (range 10-20)

14 % of samples with RV1 detected Results PCR detection of RV1 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Day post-immunization

15 Results adverse events Adverse event Up to 2 days post-immunization, n (%) Up to 7 days post-immunization, n (%) Any adverse event 12 (71%) 13 (76%) Fever 38.0 o C 1 (6%) 2 (12%) Low temperature 3 (18%) 3 (18%) Any temperature instability 4 (24%) 5 (29%) Decreased feeding 5 (29%) 5 (29%) Less active 8 (47%) 8 (47%) More irritable 3 (18%) 4 (24%) Cried persistently 2 (12%) 2 (12%) Vomiting 5 (29%) 7 (41%) Diarrhea 3 (18%) 4 (24%) Respiratory compromise 5 (29%) 6 (35%)

16 What about RV5? Quebec study Thrall et al. Vaccine (2015) - Retrospective chart review to babies in NICU receiving RV5 After immunization with RV5 - No changes in risk of gastrointestinal complications - No changes in feeding No increase in rates of hospital-acquired rotavirus infection

17 Summary 59% babies in NICU have detectable RV1 vaccine in feces at some point - Shedding at least 20 days post-immunization - Peak shedding ~2 weeks post-immunization Adverse events low Main limitation: small sample size in study Future work - Relationship of shedding to clinical data - Immunogenicity data - Studies to assess transmission

18 Acknowledgements Andrew Pollard Mark Anthony Sheula Barlow Sponsor: University of Oxford, UK Funder: University of Oxford, UK